Viral Load in Blood and Lymph Tissues of HIV-Infected Individuals

Study Overview
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Brief Summary
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Our laboratory has previously demonstrated that lymph nodes are a major reservoir for human immunodeficiency virus (HIV) and a major site of active virus replication in infected individuals. There is at least a 10 fold greater viral burden per given number of CD4+ T lymphocytes obtained from the lymph nodes versus the peripheral blood in the same infected individual. These data have been accumulated predominantly in individuals with progressive generalized lymphadenopathy (CDC Class A1 and A2). It is unclear at present whether this pattern holds true for all categories of HIV infected individuals. We have proposed that the seeding of lymph nodes by HIV early in the course of HIV infection and the persistent production of virus in lymph nodes throughout the course of infection are major factors in the pathogenesis of HIV in virtually all infected individuals. In addition, it is likely that the selective perturbations of various T cell subsets (i.e., V-B classes of CD4+T cells) that have been observed in peripheral blood are much more dramatic in the lymph node given the greater viral burden in the lymph node compared to the peripheral blood. In order to investigate this hypothesis, it is essential that we study simultaneously lymph nodes and peripheral blood from the same individuals and that we study different individuals at various stages of disease from early in the course of infection (CDC Class A) to advanced disease (CDC Class B and C). If, as we suspect, there is active virus replication in the lymph node early in the course of infection, even at a time when there is little virus burden or active replication in the peripheral blood, this would justify anti-retroviral therapy at the earliest possible time in the course of infection. In addition, in certain patients who are about to initiate treatment with an anti-retroviral agent such as zidovudine or didanosine through their private physician, it would be important to know whether treatment actually reduces the viral burden and virus replication in lymph nodes. The effect of therapy on viral burden and replication will be compared in the lymph node versus peripheral blood mononuclear cells and both of these parameters will be compared with the level of plasma viremia.

Detailed Description
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We are studying the pathogenesis of HIV infection and other immune dysfunctions. Because of the lack of an adequate animal model it is generally necessary to utilize human peripheral blood and lymphoid tissues cells for studying aspects of either in vivo or in vitro HIV infection. A dichotomy exists between the amount of HIV that can be measured in peripheral blood compared to lymphoid tissue, as well as the types of immune cells that reside in each compartment. We wish to be able to continue to elucidate many pathogenic aspects of HIV infection and other immune dysfunctions using human peripheral blood mononuclear cells and intact tissue or cells obtained from two major lymphoid organs, lymph nodes and bone marrow.

Official Title
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A Study of Viral Burden in Peripheral Blood Versus Lymphoid and Bone Marrow Tissue in HIV-Infected Individuals

Conditions
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HIV

Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: HIV infection must be documented by a licensed ELISA and confirmed either by Western blot, or plasma viremia. Aged 18 years or older. Ability to give informed, written consent. The following laboratory values: Absolute neutrophil count of greater than 1000/mm3. PT, PTT within normal limits (unless PTT is elevated in presence of positive lupus anticoagulant in a subject with no prior history of abnormal bleeding). Adequate blood counts (HIV positive volunteers: hemoglobin greater than or equal to 9.0 g/dL, HCT greater than or equal to 28%, platelets greater than or equal to 75,000; HIV negative volunteers: hemoglobin greater than or equal to 11.2 g/dL, HCT greater than or equal to 34.1%, platelets greater than or equal to 150,000). Blood pressure less than or equal to 180/100; pulse rate 50-100, unless a lower pulse rate is considered normal for the volunteer. HIV negative individuals will qualify as control subjects. Patients must have a clinically palpable lymph node in an easily accessible location. Willingness to allow blood samples to be used for future studies of HIV infection/pathogenesis, undergo genetic testing including HLA testing, and undergo hepatitis screening EXCLUSION CRITERIA: Women who are pregnant and/or breast-feeding. Currently abusing alcohol or other drugs, including narcotics or cocaine. Patients with AIDS dementia or with an AIDS related malignancy other than minimal Kaposi's sarcoma. No Aspirin or Non-Steroidal Anti-inflammatory medications (NSIADs) 7 days prior to procedure. Acetaminophen (Tylenol) is permitted at any time. Any medical condition for which the PI feels LN BX might be contraindicated. Subjects in which sedation is planned. Use of narcotics (other than as prescribed by a physician) or cocaine less than 1 week prior to the date of biopsy will be excluded.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Individuals with HIV<br>Individuals with HIV | |
| Individuals without HIV<br>Individuals without HIV | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HIV-specific B-Cell and T-cell responses | We will investigate the HIV-specific B-cell and T-cell responses in the different subsets of cells in both peripheral blood, as well as bone marrow and lymphoid tissue of HIV infected individuals | Throughout | 
| Immunoregulatory mechanisms | We wish to delineate the precise nature of the immunoregulatory mechanisms and altered homing patterns that contribute to the perturbations in the phenotype and functions of various lymphocyte subsets in peripheral blood versus the LT of HIV infected individuals. | Throughout | 
| Relative burden of HIV | The purpose of this project is to determine the relative burden of human immunodeficiency virus (HIV) and/or associated changes in hematopoiesis and immune activation as well as HIV-specific responses in the various subsets of peripheral blood mononuclear cells versus the LT and BM in individual patients with HIV infection. | Throughout | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lymph Node, Polymerase Chain Reaction (PCR), In Situ Hybridization, AIDS, Excisional Biopsy, Natural History