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(1-3). 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.

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. Several subsequent studies have shown that virologic cross talk between B cells and CD4+ T cells occurs within the microenvironment of lymphoid tissues (LT) and, to a lesser extent, between cells in lymph nodes and the peripheral blood. Recently we have demonstrated that immunosuppressive CD25+CD4+ regulatory T (Treg) cells are enriched to the LT, compared to the blood, of viremic HIV+ subjects. Furthermore, Treg cells isolated from the LT are particularly effective in suppressing HIV-specific cytolytic activity. We are currently investigating several issues related to the impact of HIV infection/replication on the immune competence and homing profiles of numerous cell types within the LT. In particular, we are also investigating the role of the negative regulatory molecules, programmed death (PD)-1 and its ligands PD-L1 and PD-L2, in the suppression of HIV-specific T cell responses and the induction of apoptosis. The interaction between PD-1 and its ligands is thought to be a major mechanism whereby T cell effector function in tissue sites is restrained. Therefore, while we have performed functional studies in this area using peripheral blood, these studies are more appropriately conducted with tissue samples. We will also pursue immunological, migrational and virologic characteristics of various cell types including B cells and their subsets and CD4+, CD8+, and NK cells in the LT and bone marrow tissue.

• HIV Infection
• Viremia

• Pantaleo G, Graziosi C, Demarest JF, Butini L, Montroni M, Fox CH, Orenstein JM, Kotler DP, Fauci AS. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature. 1993 Mar 25;362(6418):355-8.
• Pantaleo G, Menzo S, Vaccarezza M, Graziosi C, Cohen OJ, Demarest JF, Montefiori D, Orenstein JM, Fox C, Schrager LK, et al. Studies in subjects with long-term nonprogressive human immunodeficiency virus infection. N Engl J Med. 1995 Jan 26;332(4):209-16.
• Cohen OJ, Vaccarezza M, Lam GK, Baird BF, Wildt K, Murphy PM, Zimmerman PA, Nutman TB, Fox CH, Hoover S, Adelsberger J, Baseler M, Arthos J, Davey RT Jr, Dewar RL, Metcalf J, Schwartzentruber DJ, Orenstein JM, Buchbinder S, Saah AJ, Detels R, Phair J, Rinaldo C, Margolick JB, Fauci AS, et al. Heterozygosity for a defective gene for CC chemokine receptor 5 is not the sole determinant for the immunologic and virologic phenotype of HIV-infected long-term nonprogressors. J Clin Invest. 1997 Sep 15;100(6):1581-9.

• INCLUSION CRITERIA

  1. HIV infection must be documented by a licensed ELISA and confirmed either by Western blot, positive HIV culture, positive HIV antigen, plasma viremia, or second antibody test positive by a method other than ELISA.
  2. Aged 18 years or older.
  3. Ability to give informed, written consent.

  4. The following laboratory values:

     1. Absolute neutrophil count of greater than 1000/mm3.
     2. PT, PTT within normal limits.
     3. 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 12.0 g/dL, HCT greater than or equal to 38%, platelets greater than or equal to 150,000).
     4. Blood pressure less than or equal to 180/100; pulse rate 50-100, unless a lower pulse rate is considered normal for the volunteer.
  5. CD4+T cell count of any level.
  6. Patients may be receiving anti-retroviral therapy.
  7. Patients may be receiving prophylaxis for opportunistic infections.
  8. HIV negative individuals will qualify as control subjects.
  9. Patients must have a clinically palpable lymph node in an easily accessible location.

EXCLUSION CRITERIA:

1. Women who are pregnant and/or breast-feeding.
2. Currently abusing alcohol or other drugs, including narcotics or cocaine.
3. Patients with AIDS dementia or with an AIDS related malignancy other than minimal Kaposi's sarcoma.
4. Patients who have taken more than two 650 mg doses of aspirin less than one week prior to the date of biopsy.
5. Patients who have taken non-aspirin containing, non-steroidal, anti-inflammatory medications (e.g. ibuprofen, naproxen, and similar drugs) within 24 hours prior to the date of biopsy.
6. Any medical condition for which the PI feels LN BX might be contraindicated.