The HIV X-File

Almost two decades ago, four previously healthy individuals presenting with mysterious immunodeficiency were reported (Gottlieb et al., N. Engl. J. Med. 305, 1425–1431, 1981). Two years later, international scientists isolated a novel retrovirus as the probable cause of an expanding acquired immune deficiency syndrome (AIDS) epidemic (Gallo et al., Science 220, 865–867, 1983; Barre-Sinoussi et al., Science 220, 868–871, 1983). Today, we are still grappling to devise effective vaccines against the human immunodeficiency virus (HIV).HIV rapidly infects and destroys CD4+ T lymphocytes, likely following delivery from peripheral tissues or mucosal membranes to the secondary lymphoid organs by dendritic cells. Vaccine research and development strategies have therefore tended toward bolstering humoral immunity (HI) and/or cell-mediated immunity (CMI) to ensure that good defenses are already in line before HIV attempts to breach them (reviewed by Heilman and Baltimore, Nat. Med. 4, 532–534, 1998). In general, HI approaches focus on producing antibody responses that can specifically neutralize viral particles or block their entry into host cells, while CMI approaches focus on drawing the attention of CD8+ cytotoxic T lymphocytes (CTL) to virally infected cells. A common obstacle to these approaches has been the unexpected variability of HIV epitopes both in the population and arising by mutagenesis.Unfortunately, the roles played by the adaptive immune responses (HI and CMI) in the course of HIV infection remain incompletely, and often inconsistently, defined. We know, for instance, that individuals infected with HIV exhibit both of these responses in widely varying degrees throughout the disease course. Not surprisingly, infected individuals exhibit extremes of illness: some succumb rapidly while others advance so slowly (surviving asymptomatically more than 10 years after infection) as to be termed long-term nonprogressors. Even among infants born to HIV-infected mothers, accounts have surfaced for identical twins in which one child progresses rapidly to AIDS while the other child does not (Goedert, Acta Paediatr. Suppl. 421, 56–59, 1997). Many possibilities have been explored to explain phenomena such as these, from differences in certain chemokine receptors (Liu et al., Cell 86, 367–377, 1996; Martin et al., Science 282, 1907–1911, 1998) to human leukocyte antigen allotypes expressed among patients (Carrington et al., Science 283, 1748–1752, 1999). At best, they appear to explain some but not all observed immune responses (or lack thereof) to HIV. The clinical face of AIDS therefore seems nearly as diverse as the viral quasispecies that define the infection of any given individual.In light of such inconsistencies, Omar Bagasra contends in his book HIV and Molecular Immunity: Prospects for the AIDS Vaccine that pursuit of vaccines against HIV is currently advancing with only one eye open. He argues that “the research efforts on retroviruses over the past 10–15 years have focused on the mechanisms of disease production by these pathogens. Now it is time to explore mechanisms by which infected hosts defend themselves. The main postulate of this book is that evolution has created some sort of intracellular protective mechanism to specifically battle retroviruses” (p. 5).Basagra's text is not merely a critique of the trials and tribulations faced by HIV/AIDS researchers in their collective quest for answers and, ultimately, a vaccine. The book is instead a highly personal treatise that describes a new theory of immunity based upon (as he admits in the preface, p. x) years of collecting and dissecting anomalous findings. To be blunt, it is the stuff of an established scientist's dreams … and nightmares.Throughout, Bagasra reiterates the existence of an as-yet-undescribed “third arm” of immunity, which he distinguishes from both HI and CMI, capable of controlling HIV infection at the molecular level. This hypothesized “molecular immunity” depends upon expression of protective RNAs produced by CD8+ T lymphocytes or natural killer cells that can neutralize viral cDNA prior to nuclear transport and integration. He bases his theory on evidence drawn largely from studies of nonhuman primates infected with various simian immunodeficiency viruses (SIVs); many monkeys infected with strains of SIV that typically infect a different monkey species (and to which the former monkeys have not been previously exposed) tend to respond similarly as humans infected with HIV. No disease is demonstrated, however, upon infection with the concordant strain, or the virus common to a given population of monkeys. Bagasra thus builds his idea around an evolutionarily naive state of the susceptible host. This is thought to confer susceptibility to pathogenic infection only in distant host/retrovirus combinations. Assuming HIV has arisen from recombination events among various SIV strains (the precise origins of which remain unknown, though in chapter 2 the author suggests it occurred during African polio vaccine trials), humans therefore serve as ideally naive hosts in which HIV can fully unleash its pathogenic potential.But why propose an entirely novel arm of immunity to account for protection from HIV infection?: “The obvious reason for the evolution of a different protective mechanism is that retroviruses are genetic parasites that penetrate into the host genome much faster than HI or CMI can develop protective barriers” (p. 77). Considering this, rapid disease progression might be expected in 100% of clinical cases if antibodies and cytolytic CTL were the only defenses against infection, but we know that this does not occur. Bagasra discusses at length the high content of potential retroviral sequence elements occupying the diverse human genome. He then asserts that they may have been specifically retained over time, rather than excised, to play an active role in the immune system (serving as the source of proposed protective RNAs produced by CTL). Like browsing through a mug shot book at police headquarters, RNAs transcribed from these regions might “recognize” (form complexes with) the genetic material of invading retroviruses such as HIV and cripple their abilities to propagate, depending strongly upon the initial infecting dose. Has this been directly proven? No, but the theory is certainly not without appeal.Despite sounding vaguely like X-Files Agent Fox Mulder with his proposal, Bagasra's concept does appear to overlap some observations regarding the natural control of HIV infection aside from conventionally recognized HI and CMI contributions. For example, ongoing studies have demonstrated that a soluble CD8+ T cell antiviral factor (CAF) can potentially control or even prevent infection by HIV (reviewed by Levy et al., Immunol. Today 17, 217–224, 1996; Stranford et al., Proc. Natl. Acad. Sci. USA 96, 1030–1035, 1999). Briefly, the CTL-associated CAF-suppressive effect (1) is observed independently of the β-chemokines RANTES, MIP-1α, and MIP-1β; (2) is not restricted by the major histocompatibility complex; and (3) acts at the level of transcription following viral integration. In conducting similar studies, Bagasra's results argue that this soluble factor is RNA (due to the fact that in vitro protective activity is lost when RNase is included in the assays) and that it completely prevents nuclear penetration by HIV (chapter 4). However, as Brander and Walker appropriately caution us regarding CTL responses to HIV (Curr. Opin. Immunol. 11, 451–459, 1999), “the relative contributions of cytolytic and noncytolytic effector mechanisms in vivo remain elusive.”Overall, HIV and Molecular Immunity: Prospects for the AIDS Vaccine is a well-researched (with more than 800 references cited) and bold presentation of a novel concept. While most of the support is indirect and nonphysiological in nature, anyone with an interest in HIV vaccine development will benefit from the detailed historical accounts and stimulating perspective offered by Bagasra in describing his theory of molecular immunity. Although flowing in a much less organized manner than the chapters in the table of contents promised (the text is often as stream-of-consciousness as a chat over coffee in the lunchroom), the book can definitely be recommended to the patient reader. Anyone who completes it will be strongly persuaded that preventive vaccine strategies should aim to barricade viral transcription and integration, while therapeutic vaccination should aim to tap the host's innate abilities (if they exist) to control viral replication.In any case, the truth is out there … somewhere. We just need to keep both of our eyes open to recognize it.