Cellular Immune Responses and Viral Diversity in Individuals Treated during Acute and Early HIV-1 Infection

Abstract

Immune responses induced during the early stages of chronic viral infections are thought to influence disease outcome. Using HIV as a model, we examined virus-specific cytotoxic T lymphocytes (CTLs), T helper cells, and viral genetic diversity in relation to duration of infection and subsequent response to antiviral therapy. Individuals with acute HIV-1 infection treated before seroconversion had weaker CTL responses directed at fewer epitopes than persons who were treated after seroconversion. However, treatment-induced control of viremia was associated with the development of strong T helper cell responses in both groups. After 1 yr of antiviral treatment initiated in acute or early infection, all epitope-specific CTL responses persisted despite undetectable viral loads. The breadth and magnitude of CTL responses remained significantly less in treated acute infection than in treated chronic infection, but viral diversity was also significantly less with immediate therapy. We conclude that early treatment of acute HIV infection leads to a more narrowly directed CTL response, stronger T helper cell responses, and a less diverse virus population. Given the need for T helper cells to maintain effective CTL responses and the ability of virus diversification to accommodate immune escape, we hypothesize that early therapy of primary infection may be beneficial despite induction of less robust CTL responses. These data also provide rationale for therapeutic immunization aimed at broadening CTL responses in treated primary HIV infection.

Despite Biased TRBV Gene Usage against a Dominant HLA B57-Restricted Epitope, TCR Diversity Can Provide Recognition of Circulating Epitope Variants

“…Instead, we found dominant TRBV7 usage in our subjects regardless of HLA B57 subtype, results which are similar to the TCR usage previously described in B*5703 subjects (18). The reason for these discordant results is not clear, but may be due to the shorter duration of infection, or early initiation of anti-retroviral therapy during acute HIV infection in some cohorts (18,(32)(33)(34), which may influence the development of the HIV specific CD8 ϩ TCR repertoire (35,36). Our subjects were completely antiretroviral therapy naive, and were infected a mean of 13 years (range .…”

Loss of T cell responses following long-term cryopreservation

“…In the context of HIV vaccine and pathogenesis studies, repositories of banked frozen PBMC samples allow retrospective monitoring of cellular immune responses by ex vivo assays such as ELISPOT and intracellular cytokine staining. Accurate quantitation of cellular immune responses is important in such studies because these responses are thought to play an essential role in control of viral replication (Borrow et al, 1994;Rosenberg et al, 1997;Altfeld et al, 2001;McMichael and RowlandJones, 2001). Also, the design of most active phase II/III vaccine studies is to bank cells from all participants and to retrospectively use these cells to define the immunologic correlates of viral control.…”

Treatment response in acute/early infection versus advanced AIDS: equivalent first and second phases of HIV RNA decline

“…We revisited this unique dataset to compare and contrast treatment responses at the disease spectrum extremes. We hypothesized that virologic suppression would be more rapid and complete during acute than advanced disease, perhaps because of rescue of immune clearance mechanisms [13] or incomplete population of viral reservoirs [14]. …”

“…Here we found no significant difference in first phase clearance between groups, although there was a trend in advanced patients for higher mean protease inhibitor levels to correlate with more rapid virologic suppression [for indinavir (r = 0.82) and nelfinavir (r = 0.42) but not the nelfinavir metabolite (r = −0.24)]. Overall, patients with cases of undetectable levels of either protease inhibitor had longer mean time to treatment response (19.6 weeks) [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] compared with patients with always-detectable levels (15.6 weeks) [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]. …”