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Vaccination preserves CD4 memory T cells during acute simian immunodeficiency virus challenge.

ABSTRACT: Acute simian immunodeficiency virus (SIV)/human immunodeficiency virus infection is accompanied by a massive destruction of CD4 memory T cells across all the tissue compartments. These early events set the course toward disease progression and immunodeficiency. Here, we demonstrate that prior vaccination reduces this destruction during acute SIV Mac251 infection, leading to better survival and long-term outcome. Systemic vaccination with a DNA-prime recombinant adenovirus boost regimen preserved memory CD4 T cells throughout the body. The vaccine regimen induced broad CD4 and CD8 T cell responses in all tissues examined and, importantly, induced antibodies that neutralized the primary isolate of SIV used for challenge. Finally, we demonstrate that the extent of preservation of the CD4 memory compartment during the acute phase provides a strong predictor for subsequent progression to death. Our data provide a mechanism to explain clinical observations that acute-phase viral loads predict long-term disease progression and underscore the need for interventions that protect against early destruction of CD4 memory T cells during acute infection.

SUBMITTER: Mattapallil JJ

PROVIDER: S-EPMC2118314 | biostudies-other | 2006 Jun

REPOSITORIES: biostudies-other

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Vaccination preserves CD4 memory T cells during acute simian immunodeficiency virus challenge.

Mattapallil Joseph J JJ Douek Daniel C DC Buckler-White Alicia A Montefiori David D Letvin Norman L NL Nabel Gary J GJ Roederer Mario M

The Journal of experimental medicine 20060530 6

Acute simian immunodeficiency virus (SIV)/human immunodeficiency virus infection is accompanied by a massive destruction of CD4 memory T cells across all the tissue compartments. These early events set the course toward disease progression and immunodeficiency. Here, we demonstrate that prior vaccination reduces this destruction during acute SIV Mac251 infection, leading to better survival and long-term outcome. Systemic vaccination with a DNA-prime recombinant adenovirus boost regimen preserved ...[more]

PMID: 16735692

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Project description:Untreated human immunodeficiency virus (HIV) infection is characterized by depletion of CD4(+) T cells, ultimately leading to the impairment of host immune defenses and death. HIV-infected CD4(+) T cells die from direct virus-induced apoptosis and CD8 T-cell-mediated elimination, but a broader and more profound depletion occurs in uninfected CD4(+) T cells via multiple indirect effects of infection. We fit mathematical models to data from experiments that tested an HIV eradication strategy in which five macaques with a proportion of CD4(+) T cells resistant to simian-human immunodeficiency virus (SHIV) entry were challenged with SHIV89.6P, a highly pathogenic dual-tropic chimeric SIV-HIV viral strain that results in rapid loss of both SHIV-susceptible and SHIV-resistant CD4(+) T cells. Our results suggest that uninfected (bystander) cell death accounts for the majority of CD4(+) T-lymphocyte loss, with at least 60% and 99% of CD4(+) T cell death occurring in uninfected cells during acute and established infection, respectively. Mechanisms to limit the profound indirect killing effects associated with HIV infection may be associated with immune preservation and improved long-term survival.HIV infection induces a massive depletion of CD4(+) T cells, leading to profound immunodeficiency, opportunistic infections, and eventually death. While HIV induces apoptosis (programmed cell death) by directly entering and replicating in CD4(+) T cells, uninfected CD4(+) T cells also undergo apoptosis due to ongoing toxic inflammation in the region of infection. In this paper, we use mathematical models in conjunction with data from simian-human immunodeficiency virus SHIV89.6P infection in macaques (a model of HIV infection in humans) to estimate the percentage of cell death that occurs in uninfected cells during the initial period of infection. We reveal that the vast majority of cell death occurs in these cells, which are not infected. The "bystander effects" that lead to enormous reductions in the number of uninfected CD4(+) T cells may be a target for future interventions that aim to limit the extent of damage caused by HIV.

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Vaccination preserves CD4 memory T cells during acute simian immunodeficiency virus challenge.

Publications

Vaccination preserves CD4 memory T cells during acute simian immunodeficiency virus challenge.

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