Increased thymic output in HIV-negative patients after antiretroviral therapy.

OBJECTIVE: To determine the effects of antiretroviral therapy on thymic output independent of HIV infection. METHODS: Thymic output was evaluated by quantifying signal joint T-cell receptor (TCR) recombination excision circles in peripheral blood lymphocytes from HIV-negative patients undergoing prophylactic antiretroviral therapy. Additionally, effects of the HIV protease inhibitor nelfinavir were assessed in vivo on TCR-induced death of murine double-positive thymocytes. RESULTS: Five out of seven HIV-negative patients undergoing prophylactic antiretroviral therapy exhibited a dramatic increase (1-3 log10) in recent thymic emigrants containing signal joint TCR recombination excision circles while their peripheral T cell compartments remained relatively unaffected. None of the patients developed subsequent HIV infections. Interestingly, nelfinavir did not have significant effects on TCR-induced apoptosis of murine thymocytes in vivo. CONCLUSION: Antiretroviral therapy augments thymic output independent of HIV. Furthermore, nelfinavir does not dramatically affect TCR-induced thymocyte death in mice, thus central tolerance remains intact.

Differential effects of interleukin-7 and interleukin-15 on NK cell anti-human immunodeficiency virus activity.

The ability of interleukin-7 (IL-7) and IL-15 to expand and/or augment effector cell functions may be of therapeutic benefit to human immunodeficiency virus (HIV)-infected patients. The functional effects of these cytokines on innate HIV-specific immunity and their impact on cells harboring HIV are unknown. We demonstrate that both IL-7 and IL-15 augment natural killer (NK) function by using cells (CD3(-) CD16(+) CD56(+)) from both HIV-positive and -negative donors. Whereas IL-7 enhances NK function through upregulation of Fas ligand, the effect of IL-15 is mediated through upregulation of tumor necrosis factor-related apoptosis-inducing ligand. The difference in these effector mechanisms is reflected by the ability of IL-15-treated but not IL-7-treated NK cells to reduce the burden of replication-competent HIV in autologous peripheral blood mononuclear cells (PBMC) (infectious units per million for control NK cells, 6.79; for IL-7-treated NK cells, 236.17; for IL-15-treated cells, 1.01; P = 0.01 versus control). In addition, the treatment of PBMC with IL-15-treated but not IL-7-treated NK cells causes undetectable HIV p24 (five of five cases), HIV RNA (five of five cases), or HIV DNA (three of five cases). These results support the concept of adjuvant immunotherapy of HIV infection with either IL-7 or IL-15 but suggest that the NK-mediated antiviral effect of IL-15 may be superior.

Antiretroviral therapy influences cellular susceptibility to apoptosis in vivo.

It has been proposed that antiretroviral therapies (ART) possess both antiviral and immunomodulatory activities when used in HIV infected patients. Few studies have addressed whether these putative immunomodulatory effects are also seen in HIV negative patients, for example, when used for post exposure prophylaxis (PEP). We chose to evaluate immunologic function in HIV negative patients who received Nelfinavir and Combivir (AZT and 3TC) as PEP. Lymphocytes from patients taken immediately before, during, and after PEP were analyzed. No changes were seen in absolute or percent CD4 or CD8 T lymphocyte numbers, nor in markers of activation, memory, or co-stimulatory molecules. Surface expression of apoptosis-related ligands and receptors were unaltered, but apoptosis susceptibility was significantly inhibited by PEP (P less than 0.05). These data confirm in vitro that apoptosis susceptibility is altered by ART, including in HIV-negative patients who take PEP.

Attenuated T-lymphocyte response to HIV therapy in individuals receiving HMG-CoA reductase inhibitors.

PURPOSE: The protease inhibitor class of antiretroviral agents is associated with the unwanted side effect of hypertriglyceridemia, which is usually treated with either HMG-CoA reductase inhibitors (statins) or fibrates. However, since statin therapy is intrinsically immunomodulatory, we questioned whether the T-cell response of patients who received PI-based therapy plus statin differed from the response of patients on PI therapy alone or on PI therapy with a fibrate. METHOD: Retrospective cohort study. RESULTS: Thirty-five patients who had received ritonavir/saquinavir (R/S)-based antiretroviral therapy for 5 or more years were evaluated and stratified into four treatment groups: patients on R/S alone (n = 9), patients on R/S and stavudine/lamivudine (d4T/3TC) (n = 10), patients on R/S with or without d4T/3TC and statin (n = 11), or patients on R/S with or without d4T/3TC and fibrate (n = 5). All patients had suppressed levels of viral replication at all time points. T-cell responses were similar in all four groups before they were exposed to lipid-lowering agents. After the addition of lipid-lowering agents, absolute CD4 T-cell responses were lower in the statin group than in all other groups (p <.05), when measured after 6, 12, and 18 months of treatment. CONCLUSION: These data suggest that T-cell responses are influenced by the choice of anti-lipid agent and suggest that a prospective comparison is needed to determine the clinical relevance of these findings.

Vpr R77Q is associated with long-term nonprogressive HIV infection and impaired induction of apoptosis.

The absence of immune defects that occurs in the syndrome of long-term nonprogressive (LTNP) HIV infection offers insights into the pathophysiology of HIV-induced immune disease. The (H[F/S]RIG)(2) domain of viral protein R (Vpr) induces apoptosis and may contribute to HIV-induced T cell depletion. We demonstrate a higher frequency of R77Q Vpr mutations in patients with LTNP than in patients with progressive disease. In addition, T cell infections using vesicular stomatitis virus G (VSV-G) pseudotyped HIV-1 Vpr R77Q result in less (P = 0.01) T cell death than infections using wild-type Vpr, despite similar levels of viral replication. Wild-type Vpr-associated events, including procaspase-8 and -3 cleavage, loss of mitochondrial transmembrane potential (deltapsi(m)), and DNA fragmentation factor activation are attenuated by R77Q Vpr. These data highlight the pathophysiologic role of Vpr in HIV-induced immune disease and suggest a novel mechanism of LTNP.