This project was designed to investigate the cellular and molecular pathways involved in the HIV regulatory effects of host and viral factors. HIV envelope protein (gp160) was found to stimulate the production of infectious virus from HIV-infected donor?s resting CD4+ T cells, a major cellular reservoir of HIV, without inducing markers of cellular activation, division or apoptosis. In a related project, this laboratory has found that individuals with detectible HIV replication in vivo (plasma HIV RNA > 500 copies/ml) harbor phenotypically resting CD4+ T cells that spontaneously produce low levels of HIV ex vivo, suggesting that these cells are in a state of partial activation that is not manifested by the expression of markers of classical T cell activation. Molecular analyses suggest that these observations are due to qualitative alterations in the HIV-infected resting CD4+ T cells reservoir rather than simply due to quantitative changes. This phenomena is HIV specific in that HIV secreting resting CD4+ T cells are not detectible in HIV/HCV co-infected donors with chronic antigenic exposure due to very high levels of HCV viremia if their HIV plasma RNA is negative (<50 copies/ml). In longitudinal analyses, the levels of HIV secreted by this cellular population closely parallel HIV viremia and the presence of these cells in the peripheral blood appears rapidly following the detection of low levels of virus in the plasma. These data suggest that HIV or HIV gene products, such as envelope protein and nef, interact with cellular components in the host to directly or indirectly generate intracellular signaling events that are sufficient for inducing HIV expression, but not classical T cell activation, in the HIV-infected resting CD4+ T cell reservoir. Using an in vitro human lymphoid tissue (tonsil) culture model, we have found that the lymphoid tissue microenvironment supports productive HIV infection of CD4+ T cells that exhibit the phenotype of ?resting? lymphocytes in that they lack both surface (CD69, CD25, CD38 and HLA-DR) and nuclear markers (DNA synthesis, Ki67, PCNA) of classical T cell activation. X4 HIV-exposed purified resting CD4+ T cells produced HIV mRNA, p24 protein and infectious virus while maintaining a resting, non-dividing T cell phenotype when re-introduced into the microenvironment of autologous lymphoid tissue, but not when cultured alone. Pro-inflammatory cytokine antagonists and the immunosuppressive cytokines interleukin (IL)-10 and transforming growth factor (TGF)-b, but not a potent inhibitor of T cell division/ full activation (mycophenoloic acid), effectively suppress X4 HIV production from resting CD4+ T cells in the lymphoid tissue demonstrating a role for endogenous proinflammatory cytokines in driving HIV production from this cellular population. These data repudiate the paradigm that HIV production in T cells requires classical T cell activation and demonstrate that the lymphoid tissue is an ideal microenvironment for ?suboptimal? cellular activation leading to HIV replication in phenotypically resting CD4+ T cells. . HIV replication in vivo represents, in part, a balance between the maintenance of an effective HIV-specific cellular immune response and the ability of HIV to replicate at optimal levels in activated CD4+ T cells. Ex vivo phenotypic analyses and in vitro functional analyses were performed to assess the possible role of CD4+CD25+ regulatory/suppressor cells in the pathogenesis of HIV infection. CD4+CD45RA-CD25+ T cells in the peripheral blood of HIV-infected viremic, but not aviremic, donors exhibited higher levels CTLA-4 co-expression (an associated, but not exclusive, marker for this regulatory subset) as compared to cells from uninfected donors. Isolation of CD4+ T cell subsets followed by functional analyses demonstrated that removal of CD4+ CD45RA- CD25+ T cells rescued HIV p24-induced proliferative responses in PBMC from most HIV-infected donors. In most cases, re-addition of this cellular population resulted in suppression of HIV-specific proliferative responses. In addition, the removal of CD4+CD25+ cells enhanced, and their re-addition suppressed, HIV gag peptide or p24-induced intracellular IFN-g and IL-2 production from both CD4+ and CD8+ T cells. In addition, preliminary data suggest that the CD4+CD25+ regulatory suppressor cells modulate, directly or indirectly, endogenous HIV replication in cultured patient cells.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Intramural Research (Z01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Niaid Extramural Activities
United States
Zip Code
Fauci, Anthony S; Marovich, Mary A; Dieffenbach, Carl W et al. (2014) Immunology. Immune activation with HIV vaccines. Science 344:49-51
Kinter, Audrey; McNally, Jonathan; Riggin, Lindsey et al. (2007) Suppression of HIV-specific T cell activity by lymph node CD25+ regulatory T cells from HIV-infected individuals. Proc Natl Acad Sci U S A 104:3390-5
Kinter, Audrey L; Horak, Robin; Sion, Melanie et al. (2007) CD25+ regulatory T cells isolated from HIV-infected individuals suppress the cytolytic and nonlytic antiviral activity of HIV-specific CD8+ T cells in vitro. AIDS Res Hum Retroviruses 23:438-50
Nacsa, Janos; Edghill-Smith, Yvette; Tsai, Wen-Po et al. (2005) Contrasting effects of low-dose IL-2 on vaccine-boosted simian immunodeficiency virus (SIV)-specific CD4+ and CD8+ T cells in macaques chronically infected with SIVmac251. J Immunol 174:1913-21
Mavilio, Domenico; Lombardo, Gabriella; Benjamin, Janet et al. (2005) Characterization of CD56-/CD16+ natural killer (NK) cells: a highly dysfunctional NK subset expanded in HIV-infected viremic individuals. Proc Natl Acad Sci U S A 102:2886-91
Mavilio, Domenico; Benjamin, Janet; Kim, Diana et al. (2005) Identification of NKG2A and NKp80 as specific natural killer cell markers in rhesus and pigtailed monkeys. Blood 106:1718-25
Kinter, Audrey L; Hennessey, Margaret; Bell, Alicia et al. (2004) CD25(+)CD4(+) regulatory T cells from the peripheral blood of asymptomatic HIV-infected individuals regulate CD4(+) and CD8(+) HIV-specific T cell immune responses in vitro and are associated with favorable clinical markers of disease status. J Exp Med 200:331-43
Kinter, Audrey L; Umscheid, Craig A; Arthos, James et al. (2003) HIV envelope induces virus expression from resting CD4+ T cells isolated from HIV-infected individuals in the absence of markers of cellular activation or apoptosis. J Immunol 170:2449-55
Bernstein, Helene B; Jackson, Robert W; Anderson, Jean et al. (2002) The effect of elective cesarean delivery and intrapartum infection on fetal lymphocyte activation and susceptibility to HIV infection. Am J Obstet Gynecol 187:1283-9
Kinter, A; Arthos, J; Cicala, C et al. (2000) Chemokines, cytokines and HIV: a complex network of interactions that influence HIV pathogenesis. Immunol Rev 177:88-98