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Limited immunogenicity of HIV CD8+ T-cell epitopes in acute Clade C virus infection.

ABSTRACT: Human immunodeficiency virus type 1 (HIV-1)-specific CD8(+) responses contribute to the decline in acute peak viremia following infection. However, data on the relative immunogenicity of CD8(+) T-cell epitopes during and after acute viremia are lacking.We characterized CD8(+) T-cell responses in 20 acutely infected, antiretroviral-naive individuals with HIV-1 subtype C infection using the interferon-? enzyme-linked immunosorbent spot assay. Eleven of these had not fully seroconverted at the time of analysis. Viruses from plasma were sequenced within defined cytotoxic T-lymphocyte (CTL) cell epitopes for selected subjects.At approximately 28 days after estimated initial infection, CD8(+) T-cell responses were directed against an average of 3 of the 410 peptides tested (range, 0-6); 2 individuals had no detectable responses at this time. At 18 weeks, the average number of peptides targeted had increased to 5 (range 0-11). Of the 56 optimal Gag CTL epitopes sequenced, 31 were wild-type in the infecting viruses, but only 11 of 31 elicited measurable CD8(+) T-cell responses.These data demonstrate that the majority of CD8(+) responses are not elicited during acute HIV infection despite the presence of the cognate epitope in the infecting strain. There is a need to define factors that influence lack of induction of effective immune responses and the parameters that dictate immunodominance in acute infection.

SUBMITTER: Radebe M

PROVIDER: S-EPMC3156105 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Limited immunogenicity of HIV CD8+ T-cell epitopes in acute Clade C virus infection.

Radebe Mopo M Nair Kriebashnie K Chonco Fundisiwe F Bishop Karen K Wright Jaclyn K JK van der Stok Mary M Bassett Ingrid V IV Mncube Zenele Z Altfeld Marcus M Walker Bruce D BD Ndung'u Thumbi T

The Journal of infectious diseases 20110901 5

<h4>Background</h4>Human immunodeficiency virus type 1 (HIV-1)-specific CD8(+) responses contribute to the decline in acute peak viremia following infection. However, data on the relative immunogenicity of CD8(+) T-cell epitopes during and after acute viremia are lacking.<h4>Methods</h4>We characterized CD8(+) T-cell responses in 20 acutely infected, antiretroviral-naive individuals with HIV-1 subtype C infection using the interferon-γ enzyme-linked immunosorbent spot assay. Eleven of these had ...[more]

PMID: 21844303

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Project description:Multiple lines of evidence indicate that CD8 + T cells are important in the control of HIV-1 (HIV) replication. However, CD8 + T cells induced by natural infection cannot eliminate the virus or reduce viral loads to acceptably low levels in most infected individuals. Understanding the basic quantitative features of CD8 + T-cell responses induced during HIV infection may therefore inform us about the limits that HIV vaccines, which aim to induce protective CD8 + T-cell responses, must exceed. Using previously published experimental data from a cohort of HIV-infected individuals with sampling times from acute to chronic infection we defined the quantitative properties of CD8 + T-cell responses to the whole HIV proteome. In contrast with a commonly held view, we found that the relative number of HIV-specific CD8 + T-cell responses (response breadth) changed little over the course of infection (first 400 days post-infection), with moderate but statistically significant changes occurring only during the first 35 symptomatic days. This challenges the idea that a change in the T-cell response breadth over time is responsible for the slow speed of viral escape from CD8 + T cells in the chronic infection. The breadth of HIV-specific CD8 + T-cell responses was not correlated with the average viral load for our small cohort of patients. Metrics of relative immunodominance of HIV-specific CD8 + T-cell responses such as Shannon entropy or the Evenness index were also not significantly correlated with the average viral load. Our mathematical-model-driven analysis suggested extremely slow expansion kinetics for the majority of HIV-specific CD8 + T-cell responses and the presence of intra- and interclonal competition between multiple CD8 + T-cell responses; such competition may limit the magnitude of CD8 + T-cell responses, specific to different epitopes, and the overall number of T-cell responses induced by vaccination. Further understanding of mechanisms underlying interactions between the virus and virus-specific CD8 + T-cell response will be instrumental in determining which T-cell-based vaccines will induce T-cell responses providing durable protection against HIV infection.

Project description:BackgroundEarly treatment of acute HIV infection with highly active antiretroviral therapy, followed by supervised treatment interruption (STI), has been associated with at least transient control of viremia. However, the durability of such control remains unclear. Here we present longitudinal follow-up of a single-arm, open-label study assessing the impact of STI in the setting of acute HIV-1 infection.Methods and findingsFourteen patients were treated during acute HIV-1 infection and subsequently subjected to an STI protocol that required retreatment if viral load exceeded 50,000 RNA copies/ml plasma or remained above 5,000 copies/ml for more than three consecutive weeks. Eleven of 14 (79%) patients were able to achieve viral loads of less than 5,000 RNA copies/ml for at least 90 d following one, two, or three interruptions of treatment. However, a gradual increase in viremia and decline in CD4+ T cell counts was observed in most individuals. By an intention-to-treat analysis, eight (57%), six (43%), and three (21%) of 14 patients achieved a maximal period of control of 180, 360, and 720 d, respectively, despite augmentation of HIV-specific CD4+ and CD8+ T cell responses. The magnitude of HIV-1-specific cellular immune responses before treatment interruption did not predict duration of viremia control. The small sample size and lack of concurrent untreated controls preclude assessment of possible clinical benefit despite failure to control viremia by study criteria.ConclusionsThese data indicate that despite initial control of viremia, durable viral control to less than 5,000 RNA copies/ml plasma in patients following treated acute HIV-1 infection occurs infrequently. Determination of whether early treatment leads to overall clinical benefit will require a larger and randomized clinical trial. These data may be relevant to current efforts to develop an HIV-1 vaccine designed to retard disease progression rather than prevent infection since they indicate that durable maintenance of low-level viremia may be difficult to achieve.

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Limited immunogenicity of HIV CD8+ T-cell epitopes in acute Clade C virus infection.

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Limited immunogenicity of HIV CD8+ T-cell epitopes in acute Clade C virus infection.

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