A steady state of CD4+ T cell memory maturation and activation is established during primary subtype C HIV-1 infection.

AIDS Research Unit, National Institute for Communicable Diseases, Johannesburg, Gauteng, South Africa.
The Journal of Immunology (Impact Factor: 5.36). 04/2010; 184(9):4926-35. DOI: 10.4049/jimmunol.0903771
Source: PubMed

ABSTRACT The functional integrity of CD4(+) T cells is crucial for well-orchestrated immunity and control of HIV-1 infection, but their selective depletion during infection creates a paradox for understanding a protective response. We used multiparameter flow cytometry to measure activation, memory maturation, and multiple functions of total and Ag-specific CD4(+) T cells in 14 HIV-1- and CMV- coinfected individuals at 3 and 12 mo post HIV-1 infection. Primary HIV-1 infection was characterized by elevated levels of CD38, HLA-DR, and Ki67 in total memory and Gag-specific CD4(+) and CD8(+) T cells. In both HIV-infected and 15 uninfected controls, the frequency of activated cells was uniformly distributed among early differentiated (ED; CD45RO(+)CD27(+)), late differentiated (CD45RO(+)CD27(-)), and fully differentiated effector (CD45RO(-)CD27(-)) memory CD4(+) T cells. In HIV-1-infected individuals, activated CD4(+) T cells significantly correlated with viremia at 3 mo postinfection (r = 0.79, p = 0.0007) and also harbored more gag provirus DNA copies than nonactivated cells (p = 0.04). Moreover, Gag-specific ED CD4(+) T cells inversely associated with plasma viral load (r = -0.87, p < 0.0001). Overall, we show that low copy numbers of gag provirus and plasma RNA copies associated with low CD4 activation as well as accumulation of ED HIV-specific CD4(+) memory. Significant positive correlations between 3 and 12 mo activation and memory events highlighted that a steady state of CD4(+) T cell activation and memory maturation was established during primary infection and that these cells were unlikely to be involved in influencing the course of viremia in the first 12 mo of HIV-1 infection.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background. The licensing of Zostavax has demonstrated that therapeutic vaccination can help control chronic viral infection. Unfortunately, HIV therapeutic vaccine trials have shown only marginal efficacy.Methods. Seventeen HIV-infected individuals with viral loads <50 copies/ml and CD4 T cell counts >350 cells/µl were randomized to the vaccine or placebo arm. Vaccine recipients received three intramuscular injections of HIV DNA (4&emsp14;mg) coding for clade B Gag, Pol, Nef, and clade A, B, C Env, followed by a replication-deficient Ad5 boost (1010 PFU) encoding all DNA vaccine antigens, except Nef. Humoral, total T cell and CD8 cytotoxic T lymphocyte (CTL) responses were studied pre- and post-vaccination. Single copy viral loads and latently infected CD4 T cell frequencies were determined. VRC 101 is a double-blind trial registered with (NCT00270465).Results. Vaccination was safe and well tolerated. Significantly stronger HIV-specific T cell responses against Gag, Pol, and Env, with increased polyfunctionality and a broadened epitope-specific CTL repertoire, were observed post-vaccination. No changes in single copy viral load or the frequency of latent infection were observed.Conclusions. Vaccination of individuals with existing HIV-specific immunity improved the magnitude, breadth and polyfunctionality of HIV-specific memory T cell responses, but did not impact markers of viral control.
    The Journal of Infectious Diseases 03/2013; · 5.85 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Long-term non-progressors (LTNP) were identified after 10-15 years of the epidemic, and have been the subject of intense investigation ever since. In a small minority of cases, infection with nef/3'LTR deleted attenuated viral strains allowed control over viral replication. A common feature of LTNP is the readily detected proliferation of CD4 T-cells in vitro, in response to p24. In some cases, the responding CD4 T-cells have cytotoxic effector function and may target conserved p24 epitopes, similar to the CD8 T-cells described below. LTNP may also carry much lower HIV DNA burden in key CD4 subsets, presumably resulting from lower viral replication during primary infection. Some studies, but not others, suggest that LTNP have CD4 T-cells that are relatively resistant to HIV infection in vitro. One possible mechanism may involve up-regulation of the cell cycle regulator p21/waf in CD4 T-cells from LTNP. Delayed progression in Caucasian LTNP is also partly associated with heterozygosity of the Δ32 CCR5 allele, probably through decreased expression of CCR5 co-receptor on CD4 T-cells. However, in approximately half of Caucasian LTNP, two host genotypes, namely HLA-B57 and HLA-B27, are associated with viral control. Immunodominant CD8 T-cells from these individuals target epitopes in p24 that are highly conserved, and escape mutations have significant fitness costs to the virus. Furthermore, recent studies have suggested that these CD8 T-cells from LTNP, but not from HLA-B27 or HLA-B57 progressors, can cross-react with intermediate escape mutations, preventing full escape via compensatory mutations. Humoral immunity appears to play little part in LTNP subjects, since broadly neutralizing antibodies are rare, even amongst slow progressors. Recent genome-wide comparisons between LTNP and progressors have confirmed the HLA-B57, HLA-B27, and delta32 CCR5 allelic associations, plus indicated a role for HLA-C/KIR interactions, but have not revealed any new genotypes so far. Nevertheless, it is hoped that studying the mechanisms of intracellular restriction factors, such as the recently identified SAMHD1, will lead to a better understanding of non-progression.
    Frontiers in Immunology 01/2013; 4:95.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Memory CD4+ T lymphocytes in peripheral blood that express integrins α4ß7 preferentially recirculate through gut-associated lymphoid tissue (GALT), a proposed site of significant HIV-1 replication. Tregs and activated CD4+ T cells in GALT could also be particularly susceptible to infection. We therefore hypothesized that infection of these subsets of memory CD4+ T cells may contribute disproportionately to the HIV-1 reservoir. A cross-sectional study of CD4+ T cell subsets of memory CD45RO+ cells in PBMC was conducted using leukapheresis from 8 subjects with untreated chronic HIV-1 infection. Real-time PCR was used to quantify total and integrated HIV-1 DNA levels from memory CD4+ T cells sorted into integrin β7+ vs β7-; CD25+CD127low Treg vs CD127high; and activated CD38+ vs CD38-. More than 80% of total HIV-1 DNA was found to reside in the integrin β7-negative non-gut-homing subset of CD45RO+ memory CD4+ T cells. Less than 10% was found in highly purified Tregs or CD38+ activated memory cells. Similarly, integrated HIV-1 DNA copies were found to be more abundant in resting non-gut-homing memory CD4+ T cells (76%) than in their activated counterparts (23%). Our investigations showed that the majority of both total and integrated HIV-1 DNA was found within non-gut-homing resting CD4+ T cells.
    AIDS research and human retroviruses 08/2013; · 2.18 Impact Factor

Full-text (2 Sources)

Available from
May 15, 2014

Similar Publications