Correlates of Delayed Disease Progression in HIV-1-Infected Kenyan Children

Chakraborty, Rana; A-S., Morel; Sutton, John; Appay, Victor; Ripley, Ruth M.; Dong, Tao; Rostron, Tim; Ogola, Simon; Palakudy, Tresa; Musoke, Rachel; D'Agostino, Angelo; Ritter, Mary A.; Rowland‐Jones, Sarah

doi:10.4049/jimmunol.174.12.8191

Cited by 23 publications

(19 citation statements)

References 56 publications

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“…Of those individuals who survived 7 years, those infected with HIV-1A had an almost identical frequency of being an LTNP compared with non–A-infected survivors. These data support the theory that host-genetic and immunological factors may play an important role in LTNP development, and the differences seen in disease progression between HIV-1A and HIV-1D may be independent of these factors,8-10,15,24 although it is possible that these host and viral subtype factors have a synergistic effect in the establishment of long-term nonprogression.…”

Section: Discussionsupporting

confidence: 79%

Frequency of Long-Term Nonprogressors in HIV-1 Seroconverters From Rakai Uganda

Laeyendecker¹,

Redd²,

Lutalo³

et al. 2009

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Objective Studies on long-term nonprogressors (LTNP) have been conducted in the USA and Europe. This study examined the frequency of LTNPs and HIV controllers among 637 HIV-1 seroconverters in rural Uganda. Design and Methods LTNPs were defined as being infected for more than 7 years with a CD4+ T-cell count above 600 cells per microliter, and HIV controllers as having undetectable viral loads on 3 separate occasions without antiretroviral treatment. HIV-1 viral load and subtype distribution between LTNP and non-LTNP populations were determined. Results Of the HIV seroconverters, 9.1% (58/637) were LTNPs and 1.4% (9/637) were HIV controllers. LTNPs had a significantly lower viral load at set point than non-LTNP participants (P < 0.001). The Kaplan–Meier joint probability of surviving to 7 years with a CD4 count >600 was 19.2%. Individuals who survived 7 years had a significantly higher frequency of HIV-1 subtype A (P < 0.05), but seroconverters infected with HIV-1A did not have a significantly higher probability of becoming an LTNP. Conclusions The frequency of LTNPs appears to be relatively high in Uganda and it may be important to take this into account when designing studies of viral pathogenesis and performing HIV vaccine trials in sub-Saharan Africa.

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Section: Discussionsupporting

confidence: 79%

Frequency of Long-Term Nonprogressors in HIV-1 Seroconverters From Rakai Uganda

Laeyendecker¹,

Redd²,

Lutalo³

et al. 2009

JAIDS Journal of Acquired Immune Deficiency Syndromes

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“…One hallmark of long-term nonprogression in adults and children is preservation of the CD4 ϩ memory compartment (13,55). Reduction from 30,000 copies/ml to less than 1,000 copies/ml, a 1.5 log reduction, prevents transmission of HIV (27,28,52) and increases longevity (43,44,59).…”

Section: Discussionmentioning

confidence: 99%

Vaccine-Induced Cellular Immune Responses Reduce Plasma Viral Concentrations after Repeated Low-Dose Challenge with Pathogenic Simian Immunodeficiency Virus SIVmac239

Wilson

Reed

Napoé

et al. 2006

J Virol

237

226

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The goal of an AIDS vaccine regimen designed to induce cellular immune responses should be to reduce the viral set point and preserve memory CD4 lymphocytes. Here we investigated whether vaccine-induced cellular immunity in the absence of any Env-specific antibodies can control viral replication following multiple low-dose challenges with the highly pathogenic SIVmac239 isolate. Eight Mamu-A*01-positive Indian rhesus macaques were vaccinated with simian immunodeficiency virus (SIV) gag, tat, rev, and nef using a DNA prime-adenovirus boost strategy. Peak viremia (P ‫؍‬ 0.007) and the chronic phase set point (P ‫؍‬ 0.0192) were significantly decreased in the vaccinated cohort, out to 1 year postinfection. Loss of CD4 ؉ memory populations was also ameliorated in vaccinated animals. Interestingly, only one of the eight vaccinees developed Env-specific neutralizing antibodies after infection. The control observed was significantly improved over that observed in animals vaccinated with SIV gag only. Vaccine-induced cellular immune responses can, therefore, exert a measure of control over replication of the AIDS virus in the complete absence of neutralizing antibody and give us hope that a vaccine designed to induce cellular immune responses might control viral replication.

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“…In HIV-1-infected children younger than four years of age, CD8 + T cells secreting IFN-γ in response to HIV-1 peptides are low in frequency and lack breadth [27]. Researchers have attributed this to the lack of effective HIV-1-specific CD4 + T-helper responses (abnormal skewing of CD4 differentiation to a higher Th2:Th1 ratio) and deficiencies in T-cell priming and effector functions [19], [27]–[29].…”

Section: Introductionmentioning

confidence: 99%

Strong HIV-1-Specific T Cell Responses in HIV-1-Exposed Uninfected Infants and Neonates Revealed after Regulatory T Cell Removal

et al. 2006

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Background In utero transmission of HIV-1 occurs on average in only 3%–15% of HIV-1-exposed neonates born to mothers not on antiretroviral drug therapy. Thus, despite potential exposure, the majority of infants remain uninfected. Weak HIV-1-specific T-cell responses have been detected in children exposed to HIV-1, and potentially contribute to protection against infection. We, and others, have recently shown that the removal of CD4+CD25+ T-regulatory (Treg) cells can reveal strong HIV-1 specific T-cell responses in some HIV-1 infected adults. Here, we hypothesized that Treg cells could suppress HIV-1-specific immune responses in young children.Methodology/Principal FindingsWe studied two cohorts of children. The first group included HIV-1-exposed-uninfected (EU) as well as unexposed (UNEX) neonates. The second group comprised HIV-1-infected and HIV-1-EU children. We quantified the frequency of Treg cells, T-cell activation, and cell-mediated immune responses. We detected high levels of CD4+CD25+CD127− Treg cells and low levels of CD4+ and CD8+ T cell activation in the cord blood of the EU neonates. We observed HIV-1-specific T cell immune responses in all of the children exposed to the virus. These T-cell responses were not seen in the cord blood of control HIV-1 unexposed neonates. Moreover, the depletion of CD4+CD25+ Treg cells from the cord blood of EU newborns strikingly augmented both CD4+ and CD8+ HIV-1-specific immune responses.Conclusions/SignificanceThis study provides new evidence that EU infants can mount strong HIV-1-specific T cell responses, and that in utero CD4+CD25+ T-regulatory cells may be contributing to the lack of vertical transmission by reducing T cell activation.

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Correlates of Delayed Disease Progression in HIV-1-Infected Kenyan Children

Cited by 23 publications

References 56 publications

Frequency of Long-Term Nonprogressors in HIV-1 Seroconverters From Rakai Uganda

Frequency of Long-Term Nonprogressors in HIV-1 Seroconverters From Rakai Uganda

Vaccine-Induced Cellular Immune Responses Reduce Plasma Viral Concentrations after Repeated Low-Dose Challenge with Pathogenic Simian Immunodeficiency Virus SIVmac239

Strong HIV-1-Specific T Cell Responses in HIV-1-Exposed Uninfected Infants and Neonates Revealed after Regulatory T Cell Removal

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