A Record of Sustained Excellence

National Cancer Institute

U.S. DEPARTMENT 

OF HEALTH AND 

HUMAN SERVICES

National Institutes 

of Health

HIV/AIDS Research at the NCI:
HIV/AIDS Research at the National Cancer Institute: 

A Record of Sustained Excellence

Letter from the Director of the CCR ............................................................................................................1 

The Early NCI Retrovirus Experience ...........................................................................................................2

A New Virus Revealed ......................................................................................................................2 

Risk Factors........................................................................................................................................4

A Tale of Two Diseases ...............................................................................................................................5

Treating the Infection.........................................................................................................................5

Treating the Cancers .........................................................................................................................6

HIV and the Immune System: How They Interact........................................................................................8 

Susceptibility to Infection, AIDS, and Related Diseases ..........................................................................10 

Outsmarting a Formidable Foe: Viral Diversity and Drug Resistance........................................................12

HIV Variation ....................................................................................................................................12

HIV Assays.......................................................................................................................................12

The Evolution of Resistance.............................................................................................................13

Better Ways to Find Better Drugs..............................................................................................................14

Structural Biology.............................................................................................................................14

Taking Advantage of Nature’s Products...........................................................................................15

Looking Ahead: Vaccines to Prevent Infection ..........................................................................................17

DNA Vaccines ..................................................................................................................................17

Neutralizing Antibodies...................................................................................................................17

Novel Whole Inactivated Vaccines..................................................................................................18

Live Vector Vaccines........................................................................................................................19

Center of Excellence: Bringing It All Together...........................................................................................20 

The many common threads between cancer and HIV/AIDS underscore 

the value of NCI’s involvement in HIV/AIDS research.

— NCI Director John E. Niederhuber, M.D.
HIV/AIDS Research | 1

In 1981, the NIH Clinical Center admitted its first patient with acquired immune 

deficiency syndrome (AIDS) into the 

clinical service of the National Cancer 

Institute’s (NCI) Metabolism Branch. 

Since these earliest days of the deadly 

epidemic, the NCI has been a leader in 

AIDS research. NCI intramural scientists 

were able to quickly apply their expertise 

in epidemiology, cancer, retroviruses, cell 

biology, the immune system, and drug 

development to this public health crisis.

Over two decades later, their commitment 

and contributions remain strong.

The NCI intramural research program 

(IRP) is a unique nexus for basic, clinical, and translational research. Its mission 

is to forge a deeper understanding and 

to develop more effective means for the 

prevention, diagnosis, and treatment 

of cancer and AIDS. In pursuit of this goal, 

dedicated researchers work independently 

and in multi-disciplinary teams to make 

discoveries, develop new technologies and 

approaches, and translate their advances 

into clinical practice. 

The NCI IRP, which includes the Center 

for Cancer Research (CCR), has a unique 

ability to integrate multiple scientific 

disciplines and approaches in support of 

scientific discovery. Our Centers of Excellence, Faculties, Working Groups, and Programs successfully cut across organizational 

boundaries to foster collaborative research. 

The newly formed Center of Excellence 

in HIV/AIDS and Cancer Virology is one 

example of this integration.

The NCI IRP collaborates with researchers and clinicians in other NIH institutes, 

universities, medical centers, and industry. To facilitate a broader, cost-effective 

AIDS research effort, the NCI intramural 

program makes many resources developed 

here available to partners in academic 

institutions and pharmaceutical companies 

free of charge. These include: 1) highly 

purified preparations of HIV and other 

retroviruses; 2) biological reagents such as 

purified proteins, antibodies, recombinant 

DNA vectors and cell lines; 3) natural and 

synthetic small molecule libraries; 4) highly 

sensitive methods for HIV detection; and 

5) databases, including the HIV Protease 

Database and the Chemical Structure 

Lookup Service. Our resource sharing is a 

critical component of the NCI commitment to speed the development of more 

effective treatments. 

Progress against HIV infection and AIDS, 

diagnoses once perceived as an automatic 

death sentence, has been striking. Deaths 

in the United States have dramatically 

declined since the 1990s, when effective 

combination antiretroviral therapy was 

introduced. In 2005, 17,011 people died 

of AIDS in the U.S.—about one-third 

the 51,414 deaths in 1995. But major 

challenges remain. People now living 

longer with HIV are facing an increased 

cumulative risk for AIDS-related as well as 

other cancers; the pandemic of AIDS and 

AIDS-associated cancers is a devastating 

presence in developing countries; and the 

virus is notorious for outsmarting existing 

therapies. There is still much to do.

After more than two decades of important 

contributions, it seems fitting to take time 

to acknowledge and reflect on the current AIDS research effort and the many 

advances that have already been made 

within the CCR and NCI IRP, as these 

achievements serve as the foundation 

for continued scientific excellence. The 

research featured on the following pages 

demonstrates how NCI’s investment and 

sustained commitment to exploration and 

discovery has led to, and continues to lead 

to, new approaches and interventions to 

improve the lives of patients with cancer 

and HIV/AIDS.

Robert H. Wiltrout, Ph.D.

Director, Center for Cancer Research

National Cancer Institute

National Institutes of Health

Letter from the Director of the Center for Cancer Research

Dr. Robert Wiltrout
2 | National Cancer Institute

Retroviruses are unusual. Instead of the 

normal cellular process of transcribing 

genetic information from DNA into RNA, 

they use the enzyme reverse transcriptase 

to convert their RNA genome into DNA 

for integration into the host’s chromosomal 

DNA to establish infection.

After the first cases of AIDS were reported, 

Dr. Gallo’s group explored the hypothesis 

that this new disease might also be caused 

by a human retrovirus, in part because 

HTLV-1 caused immunodeficiency and 

cancer. By 1984, they showed that a new 

retrovirus could frequently be isolated in 

the blood of patients with AIDS. Drs. Luc 

Montagnier, Jean-Claude Chermann, and 

co-workers in France had just reported 

isolating a retrovirus from the blood of 

patients with an AIDS prodrome, and 

subsequent studies showed these to be the 

same virus, now called HIV (or human 

immunodeficiency virus). Drs. Gallo, 

Mikulas Popovic and other colleagues 

also developed techniques for continuous 

culture of the new virus in immortalized 

T lymphocyte cell lines and demonstrated 

that patients with AIDS had antibodies to 

this virus. In collaboration with Dr. Larry 

Arthur at NCI-Frederick, this technology 

was used to develop a blood test to protect 

the blood supply. 

After these initial discoveries, Dr. Gallo 

and colleagues including Drs. Flossie 

Wong-Staal, George Pavlakis, Barbara 

Felber, Genoveffa Franchini, George Shaw, 

Beatrice Hahn, Lee Ratner, Mark Feinberg, 

Suresh Arya, Amanda Fisher, and others 

defined many key points of the biology of 

HIV, describing the sequence of the HIV 

genome, identifying regulatory proteins of 

HIV, showing that certain strains of HIV 

could infect macrophages, and elucidating 

how viral proteins interacted with the host’s 

transcriptional and translational machinery. NCI scientists also helped describe the 

structures of viral RNAs, as well as critical 

viral enzymes. Early work by NCI scientists, including Drs. Stephen Oroszlan, 

Louis Henderson and Alan Rein, also led 

to the definition of the protein components 

The Early NCI Retrovirus Experience 

A New Virus Revealed 

In the years before AIDS appeared as a new disease, investigators in the Laboratory 

of Tumor Cell Biology, led by Dr. Robert C. Gallo, were searching for cancer-inducing 

viruses that might be responsible for human tumors. In 1980, the year before the 

first cases of AIDS were reported, Drs. Bernard Poiesz, Frank Ruscetti, Gallo, and 

colleagues at NCI discovered and characterized the first human cancer-causing 

retrovirus, HTLV-1, in a patient with leukemia/lymphoma. Soon after, they identified 

HTLV-2 as the second human retrovirus. 

From left, Dr. Genoveffa Franchini, Dr. Robert C. Gallo, Dr. Sandra Colombini, and Ershel Richardson discuss 

their research.

1980 First human retrovirus (HTLV-1): 

T Lymphocyte cell cultures and 

growth factors

1984 HIV-1 demonstrated as causative agent of AIDS: virus cloned 

and characterized

1984 Large-scale production of 

HIV-1: development of diagnostic 

blood tests
HIV/AIDS Research | 3

of virus particles, and ongoing studies have 

continued to establish the roles of these 

proteins in virus particle assembly and 

structure. Dr. Marjorie Robert-Guroff and 

colleagues also described the first neutralizing antibodies that blocked HIV infection 

and the first HIV escape mutants selected 

by such antibodies. During this same 

period, Drs. Gene Shearer, Mario Clerici, 

and colleagues conducted a number of important studies defining the immunologic 

perturbations occurring in HIV infection. 

Subsequently, Dr. Jay Berzofsky and 

colleagues discovered the first helper and 

killer T cell epitopes, facilitating work on 

HIV vaccines to induce cellular immunity.

HIV Virus Life Cycle

HIV is a retrovirus, belonging to the Lentivirus genus, 

and, like all retroviruses, replicates by copying its 

genome RNA into DNA, integrating the DNA into the 

genetic information of the host cell. Host cell machinery subsequently makes more copies of genome RNA 

and proteins, which are then assembled into infectious virions. Figure courtesy of Louis Henderson 
4 | National Cancer Institute

Risk Factors

In 1981, clinicians in New York and other 

coastal cities in the United States began 

seeing a number of cases of Kaposi’s sarcoma (KS) in young men. This disease had 

previously been extremely rare, occurring 

mostly in elderly men from Mediterranean 

countries. This outbreak of KS was one of 

the first harbingers of the AIDS epidemic. 

These observations led Drs. James Goedert, Robert Biggar, and William Blattner, 

of NCI’s Division of Cancer Epidemiology and Genetics (DCEG), to undertake 

prospective cohort studies of homosexual 

men. Data and specimens from these studies were important contributions to the 

1984 co-discovery of HIV. Through studies 

of homosexual men, people with hemophilia, injection drug users, laboratory and 

health care workers, and pregnant women 

and their offspring, these epidemiologists and their colleagues helped to define 

the major risk factors for sexual, bloodborne, occupational, and mother-to-infant 

transmission of HIV. Dr. Biggar’s studies in 

1984-85 demonstrated the extraordinarily 

high HIV prevalence in several countries of 

Africa. Along with Dr. Philip Rosenberg, 

NCI Biostatistics Branch, and colleagues, 

DCEG scientists provided data indicating 

that progression of HIV-related immune 

deficiency was inexorable and likely to be 

lethal in most cases, and that the disease 

progressed at the same rate in homosexual 

men, people with hemophilia, and all other 

risk groups. 

The team of epidemiologists and statisticians also identified and quantified the 

prognostic value of CD4+ lymphocyte 

counts. Drs. Goedert, Biggar, and Thomas 

O’Brien in the NCI Viral Epidemiology 

Branch were among the first to apply newly 

developed quantitative polymerase chain 

reaction (PCR) methods to help establish the strong relationship between HIV 

plasma viral load and subsequent risk of 

AIDS and death.

Human dermal microvascular endothelial cells infected 

with recombinant Kaposi’s sarcoma-associated herpesvirus (KSHV). Green represents latent infection and red 

represents cells undergoing lytic activation (power 10X). 

Figure courtesy of Drs. Paula Velasco and David Davis

NCI’s Role in Early Advances in HIV/AIDS Research 

n co-discovering HIV

n proving HIV as the causal agent 

of AIDS

n large scale virus culture methods 

established

n developing first blood test 

for HIV 

n discovering several of the 

regulatory proteins of HIV 

n describing the first antibodies 

to neutralize HIV

n describing the first neutralization 

escape mutants of HIV

n discovering the first helper T cell 

and cytotoxic T cell epitopes of HIV

n describing the first structures 

of HIV-1 protease and reverse 

transcriptase

1985 Discovery and location of HIV 

transcriptional activator (tat) protein 

1989 HIV rev protein demonstrated 

essential for stability and transport 

of viral mRNA

Kaposi’s sarcoma 

lesions most 

often develop 

in the patient’s 

feet because 

they are often 

hypoxic (low 

oxygen). This condition induces 

replication in KSHV-infected cells.
HIV/AIDS Research | 5

A Tale of Two Diseases 

Treating the Infection

Untreated HIV infection is one of the 

major root causes of cancer caused by 

infectious agents. During the early days of 

the epidemic, most patients with AIDSassociated cancers had extremely low CD4+ 

T lymphocyte counts and were as likely 

to die of other complications of advanced 

AIDS as from the malignancy. Successfully 

treating these tumors would require effective treatment of the underlying AIDS in 

addition to treating the tumor itself. 

And so, in the earliest days of the epidemic, 

a group of intramural researchers at the NCI 

turned their attention to developing effective 

AIDS therapy. Soon after HIV was found to 

be the cause of AIDS, Drs. Samuel Broder, 

Hiroaki Mitsuya, and Robert Yarchoan 

showed that certain nucleoside analogs had 

activity against HIV in the test tube and 

rapidly moved to test them in clinical trials 

in the NIH Clinical Center. Their work 

yielded the first drugs approved by the U.S. 

Food and Drug Administration (FDA) for 

the treatment of AIDS: zidovudine (AZT), 

didanosine (ddI), and zalcitabine (ddC). Dr. 

Phillip Pizzo and colleagues in the Pediatric 

Branch conducted some of the initial trials of 

these drugs in HIV-infected children. Today, 

such drugs, combined with protease (PR) 

and non-nucleoside reverse transcriptase 

(RT) inhibitors, form the basis for highly 

active antiretroviral therapy, or HAART. 

This therapy reverses the immune suppression caused by HIV infection and markedly 

extends the lives of HIV-infected patients. 

In addition, HAART patients benefit from 

improved prophylaxis and treatment of opportunistic infections. As a result, advanced 

AIDS and opportunistic infections have 

declined dramatically as causes of death in 

HIV-infected patients, and cancer is emerging as the most common cause of death. 

Although the risk of developing AIDSrelated malignancies that tend to occur in 

People infected with HIV face a two-pronged risk—the infection weakens the 

immune system, leading to AIDS and opportunistic infections—and HIV increases 

the risk of several cancers, including aggressive B cell lymphomas and primary 

central nervous system lymphoma. These tumors, as well as cervical cancer, confer 

a diagnosis of AIDS in HIV-infected individuals. Other tumors are also increased in 

HIV-infected patients, including Hodgkin’s lymphoma, multiple myeloma, lung 

cancer, and cancers of the liver, lip, and pharynx.

Drs. Robert Yarchoan (upper left),

Hiroaki Mitsuya (above, lower left), 

and Samuel Broder (above, lower 

right), co-discoverers of AZT and ddI. 

1985 AZT (zidovudine) blocks HIV-1 

infection & clinical trial initiated 

(approved for treatment of HIVinfected patients in 1987)

1991 ddI (didanosine) approved by 

FDA as second AIDS drug

HAART begins

New Cases

Deaths

80

100

60

40

20

0

No. of Cases/Deaths

(Thousands)

 Success of HAART for AIDS: 1985–2003

1985 1989 1993 1996 1999 2003
6 | National Cancer Institute

0

0 6 12 18 24 30 36

50

100

Prevalence (Thousands)

Months

NCI EPOCH CD4>99

NCI EPOCH 

1997-1998 (HAART)

1991-1994 (pre-HAART)

Overall Survival of AIDS-NHL: Impact of HAART and EPOCH 

Paclitaxel—space filling molecule (inset, above)—was originally extracted from the 

bark of the pacific yew tree (taxus brevifolia). Source: George McGregor. Scientists 

are trying to find alternative ways of producing this compound such as using yew 

needles. Source: Dr. Gordon Cragg

patients with very low CD4+ T lymphocyte 

counts has declined, as patients live longer, 

they have an increasing cumulative risk of 

developing a variety of other tumors. 

Treating the Cancers

Since the development of effective combination antiretroviral treatment began 

extending the lives of people with HIV, 

CCR researchers have turned their attention to the AIDS malignancies themselves. 

Drs. Barbara Ensoli, Shuji Nakamura, and 

others working with Dr. Gallo investigated 

the pathogenesis of KS and described the 

importance of angiogenic factors in this 

process. In 1995 Dr. Robert Yarchoan and 

colleagues demonstrated that paclitaxel, 

an anticancer drug that NCI played a 

critical role in discovering and developing, 

is an effective treatment for patients with 

advanced KS. Paclitaxel is now approved 

by the FDA as a second-line therapy for 

KS. More recently, Drs. Yarchoan, Richard 

Little, and co-workers in the HIV AIDS 

Malignancy Branch (HAMB) have shown 

that interleukin-12 (IL-12) has clinical 

activity in patients with AIDS-associated 

KS, and a study combining IL-12 and the 

anticancer drug liposomal doxorubicin in 

patients with advanced KS is underway.

Thanks to progress at the NCI, patients 

with AIDS-related lymphoma also face 

a brighter future. During the early days 

of the epidemic, lymphoma was rapidly 

fatal, taking patients’ lives an average of 4 

months after diagnosis. In 2003, CCR’s 

2003

Populations of AIDS Patients in the U.S. at Risk for Cancer

HAART begins

1985 1987 1989 1991 1993 1995 1997 1999 2001

450

350

250

150

50

Prevalence (Thousands)

1995 Paclitaxel active against 

Kaposi’s sarcoma: receives FDA 

approval in 1997

2003 EPOCH infusional therapy 

shown to be highly effective against 

AIDS lymphoma 

See: Besson et al. Blood. 2001; 98: 2339-2344 and Little et al. Blood. 2003; 101: 4653-4659
HIV/AIDS Research | 7

Drs. Little and Wyndham Wilson (Metabolism Branch) and colleagues demonstrated 

that a form of combination chemotherapy 

called dose-adjusted EPOCH (etoposide, 

vincristine, doxorubicin, cyclophosphamide, and prednisone) was highly effective 

against AIDS-related lymphoma. Nearly 

75% of patients had a complete response, 

and more than half were alive and disease 

free after 4 years. CCR researchers are investigating modifications of this approach 

to improve responses with less toxicity. 

Most AIDS-associated malignancies are 

caused by DNA viruses such as EpsteinBarr virus (EBV), Kaposi’s sarcoma herpesvirus (KSHV), and human papillomavirus 

(HPV). HIV-related immunosuppression 

reduces host resistance to infection and 

tumor development. Scientists have been 

studying these viruses, looking for ways 

to prevent or treat the cancers they cause. 

Recently, the FDA approved the first vaccine that protects women against HPV 

infection. This vaccine was based on work 

that was initiated by Drs. Douglas Lowy 

and John Schiller in the Laboratory of 

Cellular Oncology (LCO). Cervical cancer 

is not only an AIDS-related tumor but also 

one of the most common tumors caused 

by an infectious agent. This vaccine may 

also prevent anal cancer, which has a high 

incidence rate in AIDS patients. 

The HPV vaccine is based on research 

showing that many copies of a single 

protein from HPV (the L1 protein) 

could assemble into hollow spheres called 

virus-like particles (VLPs). VLPs are not 

infectious, but cause the body to mount 

antiviral immune responses. Immunization 

with these particles stimulated production of antibodies that prevented virus 

infection in both animals and human 

volunteers. NCI licensed the technology to 

Merck and GlaxoSmith-Kline (GSK), both 

of which have developed HPV vaccines. 

Both vaccines protect against HPV types 

16 and 18, which cause up to 70 percent 

of all cervical cancers worldwide. Merck’s 

Gardasil®, approved by the FDA in 2006, 

also protects against HPV types 6 and 11, 

which cause up to 90% of genital warts. 

In large-scale trials, the VLP vaccines were 

100% effective at preventing premalignant 

cervical changes caused by the virus types 

in the vaccines. Under the direction of Dr. 

Allan Hildesheim, the NCI is performing its own testing of the GSK vaccine in 

Costa Rica, where there is a high rate of 

cervical cancer. 

Other CCR investigators are studying the 

basic biology of KSHV and EBV to identify novel targets for therapy. Dr. Giovanna 

Tosato, LCO, has identified cytokines 

produced by KSHV-infected cells that 

promote development of primary effusion 

lymphoma, a rare tumor. Dr. Zhi-Ming 

Zheng in HAMB has been exploring the 

use of small interfering (si) RNAs to suppress HPV proteins associated with tumor 

development. Drs. Yarchoan and David A. 

Davis are developing treatment strategies 

using pro-drugs activated by viral enzymes 

that specifically target KSHV-infected 

cells. HAMB scientists are now conducting a clinical trial of these strategies to treat 

KSHV-associated multicentric Castleman’s 

disease (MCD). NCI scientists are also 

adding to our basic understanding of the 

biology of these viruses. Dr. Denise Whitby 

of the AIDS Vaccine Program (AVP) has 

demonstrated the presence of conserved 

micro-RNA sequences in KSHV isolates. 

Variation in these sequences, which are 

believed to help regulate viral gene expression, may correlate with and help explain 

different disease presentations in KSHVinfected individuals. 

Two decades of work by the groups 

of Douglas Lowy, M.D. (upper left) 

and John Schiller, Ph.D. (above right),

could help protect millions of women 

around the world from HPV’s cancerous consequences.

2006 FDA approves the first vaccine 

to prevent HPV infection 

2006 Interleukin-12 active against 

HIV-associated Kaposi’s sarcoma
8 | National Cancer Institute

Although massive infection of CD4+ T 

cells occurs during acute infection, direct 

viral pathogenesis is not believed to be 

the sole mechanism, in part because the 

number of HIV-infected CD4+ T cells 

present at any time in an infected individual is small relative to the cell depletion observed. Therefore, indirect effects 

caused by immune-mediated mechanisms 

(immunopathogenesis) likely contribute to 

the acute and ongoing depletion of these 

cells. Exposure to virus or viral proteins can 

result in pathological triggering of many 

immune system cells, limiting the effectiveness of immune responses by killing the 

cells, impairing their function, or inducing 

pathways that suppress antiviral responses. 

Dr. Gene Shearer and colleagues in the 

Experimental Immunology Branch have 

shown that the balance between protective 

and pathogenic effects of IFN-a produced 

by plasmacytoid dendritic cells (pDC) 

activated by noninfectious HIV particles 

may be tipped in favor of pathogenesis in 

HIV infection. The high proportion of 

non-infectious HIV particles present can 

trigger IFN-a-induced apoptosis of HIVexposed but uninfected CD4+ T-cells. Exposure of pDC to non-infectious HIV can 

also upregulate the immunosuppressive, 

tryptophan-catabolizing enzyme, indoleamine 2,3-dioxygenase (IDO). Culture 

of these pDC with CD4+ T cells results 

in CD4+ T cell suppression. High IDO 

expression in vivo is often associated with 

accumulation of regulatory T cells (Tregs) 

in lymphoid tissues. These immunopathogenic mechanisms can be blocked by 

small molecules that inhibit HIV-CD4 

binding, suggesting a potential use for 

inhibition of both HIV infection and immunopathogenesis. 

Mechanisms of depletion of uninfected 

CD4+ T cells are also being explored by Dr. 

Robert Blumenthal and colleagues of the 

CCR Nanobiology Program, revealing both 

mechanisms of HIV-induced bystander 

apoptosis and strategies to circumvent it. 

The group has provided the first direct 

evidence that HIV-1 gp41-mediated 

hemifusion of infected with uninfected 

cells is required and sufficient for apoptosis 

of these bystander T cells. Furthermore, 

such apoptosis is not dependent on virus 

replication but on the phenotype of the 

Env glycoprotein associated with the virus. 

Mechanistic studies show that Env-mediated apoptosis can be prevented by using 

the PR inhibitor nelfinavir and the fusion 

inhibitor enfuvirtide. This work may have 

HIV and the Immune System: How They Interact

The profound immune disruption that is the hallmark of AIDS was clear from 

evaluation of the earliest patients, and efforts to understand the underlying disease 

processes that cause this disruption remain an active area of research. HIV 

preferentially infects cells bearing the CD4 receptor, principally helper T lymphocytes, which play a critical role in orchestrating optimal immune responses. The 

progressive loss of these cells is a clinically useful marker of disease progression. 

A key and still largely unanswered question in HIV research is the basis for the 

overwhelming depletion of CD4+ T cells following viral infection and the profound 

immune suppression that occurs as disease progresses.

Electron microscopic image of a single human 

lymphocyte. Source: Dr. Triche

Dr. Gene Shearer

1985 Identification of antibodies 

that block HIV infection

1987 Identification of Helper T cell 

epitopes in HIV proteins
HIV/AIDS Research | 9

important implications for HIV-1-infected 

individuals treated with enfuvirtide and/or 

nelfinavir. Dr Frank Maldarelli, HIV DRP, 

is exploring the applicability of these findings in a clinical setting. 

Other CCR scientists including Drs. 

Thomas Waldmann (Metabolism Branch), 

Francis Ruscetti (Laboratory of Experimental Immunology), and Joost Oppenheim 

(Laboratory of Molecular Immunoregulation), have played a role in the discovery 

and characterization of immune system 

components such as natural killer (NK) 

cells and NK-T cells, as well as immune 

modulatory cytokines such as IL-2, IL-7, 

IL-15, and TGF-b. Contributions of CCR 

immunologists have stimulated the investigation of additional pathways of how HIV 

harms the immune system and laid the 

groundwork for designing preventive and 

therapeutic strategies. 

Virus-specific CD8+ cytotoxic T lymphocytes (CTLs) play a role in controlling 

viral replication. Dr. Berzofsky and colleagues have studied the impact of antigen 

specificity, receptor avidity, and anatomic 

localization on the effectiveness of CD8+ 

T cells in controlling infection, demonstrating the importance of local mucosal 

immunity. However, despite a detectable 

frequency of virus-specific CTLs during the chronic phase, the virus is never 

completely eradicated. In the absence of 

drug treatment, control of viremia during 

the chronic phase is eventually lost and 

infected individuals develop AIDS. It is 

not known why all infected cells are not 

killed by the immune system and why the 

infection is consequently never cleared, 

but mechanisms may include: (1) latently 

infected cells hiding from the immune system through lack of viral replication; (2) 

infected cells persisting in tissues where T 

cells normally do not traffic; (3) mutations 

in the viral genome leading to viral escape 

from the T cells; and (4) an insufficient 

number of virus-specific CTL limiting the 

viral control. 

Dr. Claes Ohlen of the AIDS Vaccine 

Program (AVP) is evaluating the impact 

of adoptive transfer of large numbers of 

cloned autologous virus-specific CD8+ 

CTL on acute and chronic infection in 

experiments in non-human primates. These 

studies aim to characterize the potential 

maximum efficacy of CD8+ CTLs as 

an effector mechanism for preventive or 

therapeutic vaccines. His aim is to better characterize the immunobiology of 

HIV-specific CTL in infected hosts and to 

lay the foundation for subsequent vaccine 

studies using adoptive T cell transfer in 

macaque models. 

Blood Infection Sexual Transmission

Mucosal Tissue

Immature DC

Mature DC

Lymph Vessels

Immature DC

Blood Vessels

Lymphoid Tissue

HIV

T cells

Dr. Claes Ohlen

While HIV is well known for its 

destruction of CD4+ T helper 

lymphocytes, other immune cell 

types such as dendritic cells and 

macrophages are also thought to 

play key roles in viral pathogenesis and spread. Dendritic 

cells act as immune sentinels, 

capturing invading pathogens in 

the blood and mucosal surfaces 

to process as antigens and later 

present to CD4+ T cells. However 

a sizable proportion of HIV that 

is sequestered by dendritic cells 

escapes degradation and exploits 

the interaction with T cells to 

facilitate its spread. Figure courtesy of Dr. Vineet KewalRamani

1988 Demonstration that cytotoxic 

T lymphocytes (CTL) are important in 

HIV infection
10 | National Cancer Institute

Dr. James Goedert in the Division of 

Cancer Epidemiology and Genetics 

(DCEG) with other intramural and extramural collaborators discovered in 1987 that 

progression was slower in younger than 

in older people with hemophilia. Looking closely at AIDS-defining malignancies, Drs. Goedert, Robert Biggar, Charles 

Rabkin, Eric Engels, Sam Mbulaiteye, and 

their DCEG colleagues conducted a number of epidemiologic studies exploring the 

relationship between infection with Kaposi’s 

sarcoma associated herpesvirus (KSHV), 

also called human herpesvirus-8 (HHV-8), 

and KS. This group also showed that KS 

risk is reduced with cigarette smoking, for 

reasons yet unknown. In recent years, using data from DCEG’s HIV/AIDS cancer 

match and other sources, they showed that 

use of HAART greatly reduced the risk of 

KS and of some types of non-Hodgkin’s 

lymphoma (NHL), particularly in the 

brain. Paradoxically, HAART use appears to 

increase the risk of Hodgkin’s lymphoma. 

Over the past decade, NCI scientists have 

identified variations in numerous host 

genes or gene families that affect the rate of 

disease progression and even susceptibility 

to HIV infection itself. CCR researchers 

are exploiting these results to block HIV in 

several ways. 

Genes containing variants that affect 

outcome of HIV exposure are involved 

in either the viral replication cycle or the 

innate/acquired immune response to the 

virus. Although some of these genetic effects are pronounced, most are weak and 

detectable only in large cohorts that are 

well-defined with regard to clinical parameters. Using a candidate gene approach, 

NCI scientists have identified multiple 

host genetic effects on HIV infection or 

the rate of disease progression after infection. The chemokine receptors CCR5 and 

CXCR4 are major cellular co-receptors for 

HIV. NCI investigator Dr. Michael Dean 

and others in the Laboratory of Genomic 

Diversity (LGD) were among the first 

to identify a deletion in the CCR5 gene 

(CCR5D32) that protects against infection 

in individuals homozygous for the mutation. CCR researchers also helped show 

that heterozygotes for this variant, while 

not protected against infection, progress to 

AIDS more slowly than individuals homozygous for wild type CCR5. 

This finding represents the first major 

success in identifying a genetic variant that 

affects HIV infection and has contributed 

to the development of two treatments for 

HIV infection: CCR5 antagonists, the 

first of which was recently approved by the 

FDA and monoclonal antibodies against 

the CCR5 co-receptor. Furthermore, 

CCR5D32 has subsequently been shown to 

influence susceptibility to other diseases, 

including smallpox and West Nile virusassociated encephalitis. 

Particularly strong genetic associations with 

HIV disease progression have involved 

variation in the highly variable HLA class I 

genes, which influence resistance/susceptibility to AIDS through both acquired and 

innate immune responses. These genes code 

for cell-surface proteins that present foreign 

peptides to the immune system.

The combination of a high mutation rate 

and rapid replication enables HIV to adapt 

in patients with HIV infection, in most 

cases regardless of HLA genotype. Nevertheless, specific types of HLA have been 

Susceptibility to Infection, AIDS, and Related Diseases 

Not everyone responds to HIV in the same way. Although most HIV-infected individuals 

develop AIDS within 10 years, some take only a few years, while as many as 5% 

remain relatively healthy for 15 years or more. NCI scientists are trying to decipher 

which genes are associated with progression or non-progression to AIDS and viralinduced cancers.

Dr. Mary Carrington 

1992 Host cell proteins incorporated 

into HIV-1 shown to have functional 

significance 

1997 Mutant CCR5 receptor linked 

to less rapid progression to AIDS
HIV/AIDS Research | 11

identified that confer relative increases 

in protection from or susceptibility to 

progression to AIDS in HIV-infected 

individuals. In some cases, functional 

work involving HIV antigen presentation 

by the HLA gene products has explained 

the genetic associations observed with the 

corresponding genes. Recently, several 

investigators have shown that HLA class 

I gene products interact with the highly 

variable killer cell immunoglobin-like 

receptors (KIRs), which participate in 

controlling both natural killer cells and a 

subset of T cells. Investigators in Dr. Mary 

Carrington’s laboratory showed that specific combinations of HLA gene products 

and KIRs interact synergistically in defense 

against HIV. Ongoing multi-disciplinary collaborations with investigators at 

Harvard University and the CCR Cancer 

Inflammation Program aim to understand 

how these combinations work.

Variants in other host immune response 

genes also are associated with disease 

progression. One such gene is APOBEC3G, 

which encodes a protein that inhibits viral 

replication. The HIV protein Vif suppresses 

APOBEC3G protein activity by inducing its 

degradation. The observation that a variant 

of APOBEC3G is associated with more rapid 

progression to AIDS supports developing 

inhibitors that block Vif-promoted degradation of this antiviral cellular protein. 

Complementary studies by Dr. David Derse, 

HIV Drug Resistance Program (DRP), are 

also investigating the role of APOBEC3G in 

restricting HTLV-1 infection.

In the last decade, LGD scientists have 

described 18 host genetic variants (AIDS 

restriction genes) that influence the 

outcome of HIV exposure and infection, 

discoveries that have led to novel salvage 

therapy design and implementation. 

Researchers under the direction of Dr. Stephen O’Brien have proposed a dense single 

nucleotide polymorphism scan across the 

entire human genome to search for all gene 

variants that regulate a person’s response to 

HIV/AIDS. The goal of this approach is 

to identify regulatory host genetic factors 

required for HIV infection and AIDS progression that can serve as new targets for 

therapeutic development and even genetic 

factoring in clinical trials of AIDS vaccines 

and drugs. 

Genes That Affect HIV-1 Infection and AIDS Progression

Gene Genotype Effect

CCR5 D32/D32 Prevent infection

CCR5 +/D32 Delay AIDS

CCR2 +/64I Delay AIDS

RANTES -403A/-28G Delay AIDS

HLA HLA- A,-B,-C homozygosity Accelerate AIDS

HLA B*35Px Accelerate AIDS

HLA B*57, B*27, Bw4 Delay AIDS

KIR/HLA KIR3DS1/HLA-B Bw4-80I Delay AIDS

IL-10 -592A Accelerate AIDS

APOBEC3G 186R Accelerate AIDS

DC-SIGN -336C Susceptibility to infection

TSG101 HapC Accelerate AIDS

CUL5 Cluster II haplotypes More rapid CD4+ T cell loss

1996 – 2002 Role of MHC and KIR 

in determining outcome of HIV 

infection deciphered

Microarray analysis can be used to group genes 

that are expressed at normal levels (green) or 

overexpressed (red) in individuals that are susceptible 

to HIV infection, AIDS, or related diseases. 
12 | National Cancer Institute

HIV Variation

Like all viruses, HIV can generate genetic 

diversity by mutation when it replicates, 

as well as by recombination between 

genetically distinct viruses. Using model 

cell culture systems, Drs. Vinay Pathak and 

Wei-Shau Hu, HIV DRP, have found that 

the rate of recombination depends on the 

balance between the production of viral 

DNA and the destruction of viral RNA. 

The odds of recombination depend on a 

perfect match between genetically distinct 

viruses in one region of the RNA genome 

—even one base difference between viruses 

can greatly reduce the likelihood that they 

will recombine. 

CCR scientists also have developed sensitive tools for assessing the genetic variation within HIV populations. When first 

infected, most patients have only a single 

HIV strain or clone. In contrast, studies by 

the group of Dr. Sarah Palmer, HIV DRP, 

indicate that individuals infected with HIV 

for long periods have a complex mixture of 

closely related but genetically distinct viruses 

(called a quasispecies), and that recombination among these viruses contributes substantially to this diversity. Through mutation 

and selection, this clonal virus population 

rapidly becomes diverse. Occasionally, an individual is infected with two or more viruses 

from the same quasispecies. In these cases, 

there is rapid recombination and mutation, 

leading to a much more diverse viral population. DRP researchers are investigating how 

this diversity affects disease course and the 

efficacy of antiviral therapy. 

HIV Assays

Therapy that reduces HIV to levels undetectable by standard “ultrasensitive” assays 

(less than 50 copies of virus RNA, or less 

than 25 viral particles, per milliliter of 

blood) can potentially prolong disease-free 

life indefinitely, as long as these low levels 

are maintained. HAART does not cure the 

infection. If therapy is interrupted, even 

after many years, residual virus replicates 

and viral RNA levels increase. Occasionally, therapy fails due to the appearance of 

resistant virus. 

In collaboration with Dr. John Coffin of 

Tufts University, Dr. Palmer’s group has 

developed an HIV assay that is 100 times 

more sensitive than the “ultrasensitive” assay in general use. A large study using this 

assay found that about 80% of patients on 

A major challenge in treating HIV is the virus’s ability to mutate and become resistant to therapies. The virus is also adept at living within minute reservoirs in the body 

at levels undetectable by standard assays. CCR scientists are addressing both of 

these issues with highly sensitive assays and novel animal models of disease.

Outsmarting a Formidable Foe: Viral Diversity and Drug Resistance 

Single-Genome Sequencing (SGS)

Sequence individual genomes Phylogenetic tree 

of viral DNA

Patient plasma 

sample

Detecting HIV quasispecies through single genome sequencing. cDNA produced from plasma HIV RNA is diluted to 

a single copy. From 11 to 50 single genomes are sequenced per sample and phylogenetic analyses are performed. 

Figure courtesy of Dr. Sarah Palmer

Depiction of an HIV viral particle courtesy of Dr. Louis 

Henderson

2001 Mechanistic basis of AZT 

resistance reported
HIV/AIDS Research | 13

Appearance and Decay of Nevirapine Resistance Mutations

Percent of Patients with Mutant

Months after Single-dose Nevirapine

80

100

60

40

20

0

0 2 4 6 8 10 12

long-term suppression therapy can sustain 

very low levels of virus (averaging around 2 

viral particles per milliliter of blood) for 7 

years or more. Initial experiments suggest 

that the detected virus is not a result of 

replicating virus that somehow escapes 

from the antiviral drugs. Rather, this reservoir comes from cells that were infected 

before the initiation of therapy and that 

have persisted for many years. This virus 

is the most likely source of the rekindled 

infection when therapy is halted.

The Evolution of Resistance

Treatment of HIV-positive pregnant 

women with a single dose of the RT inhibitor nevirapine is quite effective at preventing viral transmission to their newborns, 

and has been important in preventing the 

spread of HIV in Africa. However, this 

treatment also leads to the rapid generation of resistant virus in these women. A 

CCR-developed assay revealed that a 

large majority of treated pregnant women 

have detectable mutations that cause this 

resistance. The HIV DRP’s Dr. Frank 

Maldarelli is measuring the effect of these 

mutations on subsequent therapy using the 

same inhibitors. 

Evolution of HIV drug resistance is 

difficult to follow in patients with the kind 

of detail necessary to fully understand this 

important process. Carefully designed studies in experimental animals are necessary, 

but the model virus, simian immunodeficiency virus (SIV), is not sensitive to many 

commonly used anti-HIV drugs such as 

the RT inhibitor efavirenz. For this reason, 

the group of CCR investigator Dr. Vineet 

KewalRamani, HIV DRP, has developed 

an HIV-SIV hybrid virus that causes 

disease in monkeys and is fully sensitive to 

efavirenz and other RT inhibitors. Studies 

of virus replication in infected monkeys 

treated with such drugs and using the 

highly sensitive assays developed in the 

DRP are beginning to reveal important 

details of the way in which resistance 

mutations can arise and spread through a 

viral quasispecies. These studies will help 

in the design of therapeutic and preventive 

approaches to HIV infection with a lower 

chance of failure from the appearance of 

drug-resistant virus.

Dr. Vineet KewalRamani

2005 Ultrasensitive assays developed to detect patient virus and 

drug resistance

2007 Monkey model for HIV 

resistance evolution developed
14 | National Cancer Institute

Structural Biology 

Detailed structures of HIV proteins 

are important for understanding their 

function in virus replication as well as 

their interaction with antiviral drugs. 

Knowledge gained through this process 

is also critical to the development of 

improved therapeutics and understanding 

the mechanisms by which HIV acquires 

resistance. CCR scientists Dr. Alexander 

Wlodawer, Macromolecular Crystallography Laboratory (MCL), and Dr. Stephen 

Hughes, HIV DRP, have played a key 

role in elucidating the structures of the 

enzymes PR, RT, and integrase (IN), that 

are essential for HIV replication. 

In 1989, the Wlodawer group reported 

the first structure of HIV-1 PR bound to 

a substrate-based inhibitor and since then 

has provided important information on 

drug-resistant variants of this enzyme. At 

the same time, his group has studied the 

related enzymes of Rous sarcoma, feline 

immunodeficiency, and human T-cell 

leukemia viruses. The MCL also established 

and maintains the HIV Protease Database 

which is available online to researchers, 

educators, and students. 

Subsequently Dr. Hughes’ group, 

together with Dr. Edward Arnold, Rutgers 

University, published in 1993 the first 

high-resolution structure of HIV-1 RT 

containing double-stranded DNA. This 

long-standing collaboration has made 

important contributions to our understanding of the structural and biochemical 

basis for the action of, and resistance to, 

RT inhibitors. For example, they showed 

that mutations conferring resistance to 

AZT create a binding site for the energy 

molecule ATP on HIV RT. Bound ATP 

mediates a reaction promoting DNA 

synthesis in reverse. This leads to removal 

of the drug from the growing DNA chain 

which allows viral DNA synthesis (and 

viral replication) to continue. 

Several drugs interrupt reverse transcription by mimicking nucleotides and inserting themselves into viral DNA, rendering 

it useless. However, the ribonuclease H 

(RNase H) activity of reverse transcriptase—which removes viral RNA from 

RNA-DNA duplexes—is also essential 

for viral DNA synthesis, but has received 

little attention as an antiviral target. 

CCR scientists Drs. Stuart Le Grice, HIV 

DRP, and John Beutler, Barry O’Keefe, 

and Kirk Gustafson, Molecular Targets 

Development Program (MTDP), have 

identified several classes of RNase H 

inhibitors. In collaboration with extramural scientists in the United Kingdom and 

the United States, co-crystals of HIV RT 

with two inhibitors have been obtained, 

providing an important platform for 

lead optimization.

The CCR Laboratories of Molecular 

Pharmacology (LMP) and Medicinal 

Since initial testing of AZT, ddI, and ddC, NCI researchers continue to search for 

new anti-HIV drugs. Multi-disciplinary collaborations are exploring the structures 

of viral proteins, the interaction of these proteins with antiviral drugs, and, finally, 

testing natural products that exhibit strong inhibition of HIV.

Structure of HIV-1 RT (green) bound to the inhibitor 

TMC278-rilpivirine (blue). Figure courtesy of Drs. 

Kalyan Das and Edward Arnold, Rutgers University

Better Ways to Find Better Drugs

Structure of 

PR with the 

inhibitor ritonavir in cyan 

(right) from 

Dr. Alexander 

Wlodawer 

(below)

1989 Structure of an inhibitor bound 

to HIV-1 protease solved 

1993 Structure of HIV-1 reverse 

transcriptase bound to doublestranded DNA solved
HIV/AIDS Research | 15

Chemistry (LMC) have been instrumental in drug discovery and structural 

biology. The LMP-LMC collaboration is 

among the world’s most productive for 

the discovery of inhibitors of the HIV 

IN. Most current drug regimens block either RT or PR. Dr. Yves Pommier’s group 

(LMP) was among the first to evaluate IN 

inhibitors, providing mechanistic clues 

for developing drugs presently undergoing clinical trials. Dr. Pommier’s group 

also has contributed novel biochemical 

assays to probe IN-DNA-drug interactions. Lastly, the first crystal structures for 

the catalytic core domain of IN containing divalent metal were reported by the 

Wlodawer group, while an MCL-LMP 

collaboration provided the first highresolution structure of an IN inhibitor 

bound to the enzyme.

Taking Advantage of 

Nature’s Products

MTDP and Natural Products Branch 

researchers have isolated several anti-HIV 

agents from natural product extracts. 

Working with industrial and academic 

partners, potent analogs have been developed and tested in animal models, and 

some have moved into clinical studies.

Cyanovirin and scytovirin, isolated from 

the blue-green algae Nostoc ellisosporum and 

Scytonema varium, respectively, act against 

a broad spectrum of laboratory and clinical 

HIV strains. Both block replication by 

binding to specific carbohydrate groups on 

the viral envelope glycoprotein. In collaboration among IRP groups, the structures of 

both inhibitors have been obtained using 

nuclear magnetic resonance imaging and 

x-ray diffraction. Collaborative studies 

have also shown that cyanovirin controls 

replication in a macaque-based anti-SIV 

topical microbicide model system. Griffithsin, derived from a red algae, Griffithsia 

sp., is extremely potent against both HIV-1 

and HIV-2. Griffithsin functions similar to 

cyanovirin and scytovirin, but has a greater 

number of carbohydrate binding sites, 

which may explain its enhanced potency.

NMR Structure of 

Scytovirin (right) 

from Dr. R. Andrew 

Byrd (above)

1997 Cyanovirin-N identified as 

HIV-1 entry inhibitor 

Darunavir (Prezista®), a novel PR inhibitor developed by Dr. Hiroaki Mitsuya, 

HAMB, and Purdue University scientists, was granted accelerated FDA approval 

in 2006 for treatment of AIDS patients failing to respond to existing therapies. Current PR inhibitors bind at the active site and prevent release of structural proteins 

from larger precursors, resulting in non-infectious virions. However, mutations 

can easily change the structure of the active site, rendering such drugs ineffective. Darunavir’s advantage is that it binds tightly to portions of PR that 

change little, even with viral mutations that render PR insensitive to 

other inhibitors.
16 | National Cancer Institute

A constant challenge to HIV therapy is 

developing therapeutics that are effective 

against drug-resistant virus. Following a 

collaborative venture between HIV DRP 

researcher Dr. Eric Freed and Panacos 

Pharmaceuticals, Gaithersburg, MD., 

clinical trials are underway for bevirimat, 

a derivative of betulinic acid originally 

extracted from a Taiwanese herb. Bevirimat induces changes in HIV by interfering 

with proteolytic processing of the gag precursor polypeptide into structural proteins, 

leading to defective virus particles. Bevirimat is also effective against drug-resistant 

HIV-1 strains. Results from clinical studies 

suggest that resistance to bevirimat does 

not emerge as rapidly as resistance to other 

antivirals. Dr. Freed’s group plans to define 

bevirimat resistance more precisely and to 

evaluate its efficacy against HIV-1 strains 

resistant to PR inhibitors. If further clinical 

testing is encouraging, an application for 

FDA approval is scheduled for 2008. 

Dr. Eric Freed

2006 FDA approves the HIV protease 

inhibitor Darunavir (Prezista)

Bevirimat blocks the cleavage of SP1 from the c-terminus of CA, disrupting virus maturation. 

Figure courtesy of Dr. Catharine Adamson

MA CA

SP1

NC

SP2

p6

PA-457 PA-457 treated

p55Gag

Untreated

Griffithsia sp., the red algae from which griffithsin 

was isolated. Photograph and structure courtesy 

of Dr. David Newman and Dr. Alexander 

Wlodawer, respectively
HIV/AIDS Research | 17

Looking Ahead: Vaccines to Prevent Infection 

To achieve meaningful protection, a 

vaccine must therefore elicit broad, crossreactive immune responses capable of 

protecting against multiple variants. A 

further challenge is the fact that the HIV 

envelope glycoprotein is extensively masked 

with sugars and shows extensive variation; 

epitopes that are targets of broadly neutralizing antibodies are sequestered and not 

easily recognized by the immune system. 

With these issues in mind, NCI researchers are exploring several vaccine strategies 

designed to elicit the required cellular (T 

cells) and humoral (antibody) immunity 

prior to infection.

DNA Vaccines

Drs. George Pavlakis and Barbara 

Felber, Vaccine Branch (VB), are working to enhance cellular immune responses 

by developing DNA vaccines with genes 

designed for high-level production of 

HIV proteins, combined with DNA for 

cytokines as molecular adjuvants, to induce 

strong antiviral immune responses. Dr. 

Jay Berzofsky, VB, has shown that longlived, high-avidity cytotoxic T lymphocytes (CTLs) can control HIV viremia, 

and that development of such CTLs can 

be enhanced by IL-15. Together these 

researchers are exploring a vaccine strategy 

in which DNAs encoding both IL-15 and 

HIV genes are co-administered, eliciting 

the potent cellular immunity needed to 

maintain low viral burdens. Synthetic HIV 

protein fragments (peptides) are also being 

used together with IL-15 and other molecules, which regulate immune responses in 

order to increase vaccine potency.

Neutralizing Antibodies

Dr. Dimiter Dimitrov, CCR Nanobiology 

Program has identified several unique 

cross-reactive antibodies against HIV-1 

and other viruses including SARS CoV, 

Hendra, and Nipah viruses, and used 

molecular engineering to optimize these 

Vaccines are undoubtedly the most effective method for controlling viral infections 

and epidemics. However, HIV presents unique challenges. The virus integrates 

into the DNA of an infected host cell, ensuring that infection persists for the life of 

that cell. This property of integration also allows the virus to exist in a latent state, 

hidden from the immune system, thus favoring its persistence. In addition, just as 

the virus mutates to become resistant to drugs, the continuous selection of variants 

in the face of immune responses leads to enormous diversity in HIV strains, both 

worldwide and even within a given infected individual over time.

Dr. George Pavlakis

1993 NC protein targeted for 

chemical inactivation of HIV-1 as 

vaccine candidate

Vaccines offer the hope of an effective means to 

control HIV infection.
18 | National Cancer Institute

antibodies. A comparative analysis of the 

sequences of these antibodies suggested a 

novel challenge in the development of an 

efficacious HIV vaccine—lack or limited 

availability of B cells with appropriate 

receptors. Dr. Dimitrov’s group has also 

developed one of the most potent and 

broadly cross-reactive antibodies against the 

HIV-1 envelope glycoprotein. Commercial 

development of this antibody is underway. 

Novel Whole Inactivated Vaccines

Dr. Jeffrey Lifson and colleagues in the AVP 

have developed a novel procedure to render 

HIV-1 noninfectious. This strategy arose 

from basic studies by Drs. Lou Henderson, 

Rob Gorelick, Larry Arthur, and Elena 

Chertova showing that viral replication 

depends on highly conserved sequences 

in certain sections of the nucleocapsid 

(NC) protein encoded by the HIV gag 

gene. Exploiting the intrinsic chemistry of 

retroviruses, the group developed specific 

chemical treatments that preferentially 

covalently modify interior proteins of the 

virus (including NC), eliminating infectivity. In contrast to conventional methods of 

viral inactivation, this approach leaves the 

immunologically important viral envelope 

glycoproteins structurally and functionally 

intact. These inactivated virions are being 

used extensively as reagents in immunologic assays and studies of basic viral 

biology, while CCR scientists are exploring 

their potential as vaccine immunogens in 

non-human primate models. 

Most recently, Dr. Sriram Subramaniam, 

of CCR’s Laboratory of Cell Biology, 

working with Dr. Lifson, used advanced 

3-D electron microscopy to examine the 

initial interactions between HIV and susceptible host cells, identifying a consistent 

structure, named the “entry claw,” that 

appears to consist of molecules on the surface of the virus interacting with receptors 

on the host cell membrane. Further study 

Contact of HIV-1 with T cells. Electron tomographic analysis (left) reveals the architecture of the virus-cell contact region which forms an “entry claw” as shown in the 

schematic (right). Figure courtesy of Dr. Sriram Subramaniam

Structure of aldrithiol-2, a chemical treatment 

which covalently modifies internal, but not surface, 

HIV proteins. Figure courtesy of Dr. Michal Legiewicz 

1997 Replication-competent 

adenoviral vector vaccines protect 

chimpanzees from HIV infection

2002 Systemic immunization with 

poxvirus vaccine induces mucosal 

T cell responses
HIV/AIDS Research | 19

of this structure should offer important 

clues for designing improved anti-HIV 

therapies aimed at blocking virus-target 

cell interactions.

Live Vector Vaccines

Poxviruses have been exploited extensively as vaccine vehicles. Dr. Genoveffa 

Franchini, VB, has advanced this approach 

to prevent infection as well as for therapy. 

Dr. Franchini has demonstrated protective efficacy of two vaccines in non-human 

primates infected with SIV and HIV using 

naturally attenuated (or weakened) canarypox and molecularly attenuated vaccinia 

(cowpox) virus vectors. Immunization of 

SIV-infected macaques in combination 

with suppressive antiviral therapy followed 

by cessation of the drug regimens led to 

prolonged intervals of low virus levels. 

As HIV is primarily a sexually transmitted 

disease, vaccines must induce potent immunity at rectal and genital sites. 

The Vaccine Branch’s Dr. Marjorie 

Robert-Guroff uses adenovirus (Ad) 

vectors for vaccine development. These 

vectors infect the epithelial cells lining the 

airways and gastrointestinal tract, inducing mucosal and systemic immune responses. A comparative study of replicating and non-replicating adenovirus vectors 

in non-human primates established that 

replicating Ad-HIV recombinants more 

effectively primed antibody responses 

and elicited more potent and persistent 

cellular immunity. A combination regimen involving initial Ad-recombinant 

administration followed by immunization with HIV envelope protein induced 

broadly reactive, functional antibodies 

that neutralized a spectrum of HIV clade 

B isolates, the type found in the United 

States. The antibodies also mediated 

antibody-dependent cellular cytotoxicity, 

killing cells infected with the more diverse 

HIV strains present worldwide. 

In preclinical studies, the replicating 

Ad-based strategy has elicited potent, 

durable protection against HIV isolates 

and virulent SIV. As a first test in humans, 

a phase I trial of this strategy in HIVnegative volunteers will be conducted at 

the NIH Clinical Center in collaboration 

with the National Institute of Allergy and 

Infectious Diseases. 

Adenovirus Graphic © Russell Kightley, Russell 

Kightley Media, Canberra, Australia

Marjorie Robert-Guroff, Ph.D. The pill she is holding is a prototype version of the adenovirus-based HIV vaccine. 

2005 Mucosal vaccine delays virus 

dissemination from the mucosal 

site of transmission in a non-human 

primate model
20 | National Cancer Institute

Although this brochure captures only 

a limited number of seminal contributions made by former and current 

NCI researchers, it nonetheless highlights an uninterrupted, institutional 

investment in retrovirus biology for 

more than three decades, with particular emphasis on combating HIV 

infection. While we can be proud of 

these achievements, the sobering fact 

remains that the number of newly 

HIV-infected adults and children rose 

globally from ~3.9 million in 2004 

to ~4.3 million in 2006, and the 

number of deaths from ~2.7 million 

to ~2.9 million over the same period. 

The initial successes of highly active 

antiretroviral therapy (HAART) are 

also being threatened by the rapid 

emergence of drug-resistant virus, 

placing a constant demand for the 

continuous development of alternative and more effective therapeutic 

and immunological interventions. 

Recent evidence also suggests that 

the increased life expectancy of 

HIV-infected individuals on HAART 

may enhance their cumulative risk of 

developing both AIDS-defining and 

non-defining cancers (such as lung 

cancer, Hodgkin’s lymphoma, and 

anal carcinoma). In addition to the 

important role of these pathogens in 

the global HIV/AIDS epidemic, approximately one in every five human 

cancers is caused by infectious agents, 

with an estimate of 1.9 million cases 

per year worldwide. Of these, approximately 70% are caused by viruses such 

as human papilloma virus, type B and 

C hepatitis viruses, Epstein-Barr virus, 

and human T-cell leukemia virus.

As part of an NCI response to these 

formidable problems, the Center for 

Cancer Research has established the 

Center of Excellence in HIV/AIDS 

and Cancer Virology (CEHCV). 

As one of several new Centers, the 

CEHCV will coordinate existing 

structures and areas of expertise across 

the NCI-Frederick and Bethesda 

campuses as a means of rapidly communicating advances in the discovery, 

development, and delivery of antiviral 

and immunologic approaches for 

prevention and treatment of HIV 

infection, AIDS-related malignancies, 

and cancer-associated viral diseases. 

The CEHCV will also be challenged 

to lead new initiatives, projects, and 

collaborations, thereby positioning 

the IRP to play a significant role in 

interdisciplinary and multi-disciplinary 

translational research.

A strong research program within 

the NCI should also seek to nurture 

partnerships and take advantage of 

complementary expertise of researchers across the NIH and within the 

extramural community. The CEHCV 

endorses NCI’s longstanding commitment to making reagents and resources available, both nationally and 

internationally, as a means of diversifying the strategies that can be applied 

to these devastating diseases and of 

facilitating further efforts in this area. 

Finally, continuing the outstanding 

quality of basic and clinical research 

within the NCI requires a commitment to mentoring junior colleagues 

at all levels. In my opinion, the 

strongest testament to our personal 

accomplishments as scientists is how 

well we have prepared the next generation for the challenges ahead. In the 

current, highly competitive funding 

environment, our involvement and 

support will be crucial to their success. 

Participation of CEHCV members in 

events planned for the coming years 

will be essential to such endeavors, 

and I am confident that we can rise to 

these challenges. 

Stuart F. J. Le Grice, Ph.D.

Head, Center of Excellence in 

HIV/AIDS and Cancer Virology

National Cancer Institute 

National Institutes of Health

Center of Excellence: Bringing It All Together

Center of Excellence in

HIV/AIDS and Cancer Virology

Dr. Stuart Le Grice
The CEHCV is committed to supporting and training the next generation of 

HIV/AIDS and cancer virology researchers, helping launch careers in science, 

and enabling established investigators to 

pursue investigator-initiated research. The 

CEHCV works to create a high-quality 

research environment for scientists and 

clinicians. Training young investigators 

to address complex scientific questions 

through collaboration and multi-disciplinary approaches is a major goal of the 

CEHCV. Trainees at the CEHCV have the 

unique opportunity to learn from experts 

with world-class reputations in basic 

virology, biochemistry, structural biology, 

genetics, drug discovery and development, 

antiviral resistance, vaccine development, 

and epidemiology in one of the world’s 

leading scientific institutions. Current 

openings for postdoctoral fellows, staff 

scientists and research fellows in any 

CEHCV laboratory in the CCR can be 

found online at http://ccr.cancer.gov/careers/

positions.asp while other opportunities 

within the NCI can be found at 

http://www.cancer.gov/researchandfunding/

intramural.

Training Opportunities within the Center of 

Excellence in HIV/AIDS and Cancer Virology

1987 Established AIDS Vaccine 

Program at Frederick 

Cancer Research and 

Development Center

1993 HIV/AIDS Cancer Match 

established 

1995 Established AIDS 

Malignancy Consortium to 

develop approach for the management of cancers in 

HIV-positive individuals

1995 Linked AIDS data and 

Cancer Registries

1995 Established AIDS Cancer 

Specimen Resource to distribute tissues from AIDS patients 

for basic, translational, and 

epidemiological research

1996 Established intramural HIV and 

AIDS Malignancy Branch 

1997 Established the HIV Drug 

Resistance Program at 

NCI-Frederick

2005 Established Office of AIDS 

Malignancy Program at the NCI

2007 Established Center of 

Excellence in HIV/AIDS 

and Cancer Virology

Organizational Investments 

of the NCI
NIH Publication No. 07-6284

Printed October 2007

The Center of Excellence in 

HIV/AIDS and Cancer Virology

The CEHCV is composed of members from 

across the NCI’s different branches, laboratories, and programs. Current research is being 

conducted in the areas of AIDS malignancies, 

HIV virology and molecular pathogenesis, 

immunology/immunopathology, vaccines and 

immunotherapy, epidemiology, drug development/resistance, and cancer virology.

Our Mission

The mission of the Center of Excellence in 

HIV/AIDS and Cancer Virology (CEHCV) is to 

facilitate and rapidly communicate advances 

in the discovery, development, and delivery 

of antiviral and immunologic approaches for 

the prevention and treatment of HIV infection, 

AIDS-related malignancies, and cancerassociated viral diseases. 

For more information on the 

CEHCV, the CCR, or NCI please visit: 

http://ccr.ncifcrf.gov/initiatives/CEHIV/ 

http://ccr.cancer.gov/

http://www.cancer.gov/