Failure of T-cell homeostasis preceding AIDS in HIV-1 infection

Margolick, Joseph B.; Muñoz, Álvaro; Donnenberg, Albert D.; Park, Lawrence P.; Galai, Noya; Giorgi, J.; O’Gorman, Maurice R.G.; Ferbas, John

doi:10.1038/nm0795-674

Cited by 225 publications

(148 citation statements)

References 21 publications

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“…Our observation of the upward trajectories of average CD8 cell count after HIV seroconversion is consistent with previous findings from MACS [Margolick et al, 1995]. The observed positive association between tobacco smoking and CD4 cell count was previously reported by Park and colleagues [Park et al, 1992], who found that the effect of tobacco smoking on CD4 cell count was non-specific, maximal in HIV-uninfected men, and lost three years after seroconversion.…”

Section: Discussionsupporting

confidence: 92%

Recreational drug use and T lymphocyte subpopulations in HIV-uninfected and HIV-infected men

Chao

Jacobson

Tashkin

et al. 2008

Drug and Alcohol Dependence

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The effects of recreational drugs on CD4 and CD8 T cells in humans are not well understood. We conducted a longitudinal analysis of men who have sex with men (MSM) enrolled in the Multicenter AIDS Cohort Study to define associations between self-reported use of marijuana, cocaine, poppers and amphetamines, and CD4 and CD8 T cell parameters in both HIV-uninfected and HIV-infected MSM. For the HIV-infected MSM, we used clinical and laboratory data collected semiannually before 1996 to avoid potential effects of antiretroviral treatment. A regression model that allowed random intercepts and slopes as well as autoregressive covariance structure for within subject errors was used. Potential confounders adjusted for included length of follow-up, demographics, tobacco smoking, alcohol use, risky sexual behaviors, history of sexually transmitted infections, and antiviral therapy. We found no clinically meaningful associations between use of marijuana, cocaine, poppers, or amphetamines and CD4 and CD8 T cell counts, percentages, or rates of change in either HIVuninfected or -infected men. The regression coefficients were of minimum magnitude despite some reaching statistical significance. No threshold effect was detected for frequent (at least weekly) or continuous substance use in the previous year. These results indicate that use of these substances Correspondence and reprint request should be addressed to:

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Section: Discussionsupporting

confidence: 92%

Recreational drug use and T lymphocyte subpopulations in HIV-uninfected and HIV-infected men

Chao

Jacobson

Tashkin

et al. 2008

Drug and Alcohol Dependence

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“…In this vein, the immune responses induced by the bicistronic gp120-⌬Tat DNA vaccine mimicked events that occur in individuals chronically infected with HIV-1, who develop subsets of HIV-1-specific CD8 ϩ T cells that express IFN-␥ but lack cytotoxic effector functions (48,49). The immune-modulating activity of the bicistronic gp120-Tat DNA vaccine resembles events that occur in chronically infected individuals who undergo a change in clinical status concomitantly with the loss of HIV-1-specific CD8 ϩ T cells (52,53). Furthermore, the gradation of potencies displayed by the Tat DNA vaccines used in our study suggests that the degree to which CD8 ϩ T cell responses are altered by Tat depends on the bioactivity of Tat present in immune inductive sites.…”

Section: Discussionmentioning

confidence: 55%

A Tat subunit vaccine confers protective immunity against the immune-modulating activity of the human immunodeficiency virus type-1 Tat protein in mice

Agwale

Shata²,

Reitz³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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The rational design of new therapies against HIV-1 necessitates an improved understanding of the mechanisms underlying the production of ineffective immune responses to HIV-1 in most infected individuals. This report shows that the CD8 ؉ T cell responses to gp120 were greatly diminished in mice vaccinated with a bicistronic gp120-Tat DNA vaccine, compared with those induced by a DNA vaccine encoding gp120 alone. The CD8 ؉ T cell responses induced by the latter included strong gp120-specific IFN-␥ secretion and protective antiviral immunity against challenge by a vacciniaenv pseudotype. The degree to which Tat influenced CD8 ؉ T cell responses depended on the bioactivity of Tat. Thus, a bicistronic DNA vaccine that expresses gp120 and a truncated Tat defective for LTR activation elicited strong IFN-␥ -secreting CD8 ؉ T cell responses to gp120 but conferred only marginal protection against the vaccinia-env challenge. The effect of Tat was completely blocked, however, by immunization with inactivated Tat protein before vaccination with the bicistronic gp120-Tat DNA vaccine.HIV-1 ͉ immune response ͉ CD8 ϩ T cell ͉ regulation

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“…The most striking result is that among all of the immunologic and virologic variables assessed in this observational study, the only significant difference during the first months of life and before the onset of PE are the CD8 ϩ T-lymphocytes. Cytotoxic CD8 ϩ T-lymphocytes (CTLs) kill virusinfected cells, and their role in the control of HIV-1 infection in vitro and in vivo is well established, although only a few studies have analyzed their prognostic value in the follow-up of infected adults [32][33][34] and children. 21,35,36 The suppression of HIV-1 replication is dependent on the presence of a relatively small number of HIV-1-specific CD8 ϩ Tlymphocyte clones, and it is possible that the duration of the neurologically asymptomatic phase for any given child may depend mostly on the magnitude of specific CD8 ϩ T-lymphocyte responses.…”

Section: Discussionmentioning

confidence: 99%

Low Blood CD8+ T-Lymphocytes and High Circulating Monocytes Are Predictors of HIV-1-Associated Progressive Encephalopathy in Children

et al. 2003

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ABSTRACT. Objective. Human immunodeficiency virus type 1 (HIV-1)-associated progressive encephalopathy (PE) is a common and devastating complication of HIV-1 infection in children, whose risk factors have not yet been clearly defined. Regardless of the age of presentation, PE shortens life expectancy. Paradoxically, as survival of patients has been prolonged as a result of the use of antiretroviral therapy, the prevalence of PE has increased. Therefore, a predictive marker of PE emergence is critical. The objective of this study was to determine in an observational study whether any immunologic (CD4 ؉ and CD8 ؉ T-lymphocyte counts, monocyte counts) or virologic (viral load [VL], biological characteristics of viral isolates) marker might be predictive of PE and whether any particular marker may be involved in the timing of clinical onset of PE.Methods. A total of 189 children who were vertically infected with HIV-1 were studied retrospectively, 58 of whom fulfilled criteria of the American Academy of Neurology for PE. T-lymphocyte subsets and monocytes in peripheral blood were quantified by flow cytometry. HIV-1 RNA was measured in plasma using a quantitative reverse transcriptase polymerase chain reaction assay. Demographic, clinical, and viro-immunologic characteristics in infants were compared with control groups using logistic regression. Proportions were compared using the 2 test or Fisher exact test. For each child, immunologic and virologic markers were analyzed in parallel closely before clinical onset of PE and closely after PE onset and compared by using the Student t test for paired samples.Results. Overall, mortality of 58 HIV-1-infected children who developed PE was significantly higher than of children who did not develop this complication. Blood CD8 ؉ T-lymphocytes <25% in the first months of life suggested a relative risk of progressing to PE 4-fold higher than those with CD8 ؉ >25% (95% confidence interval: 1.2-13.9) and remained statistically significant after adjustment for treatment. When we compared the PE-positive group with the acquired immunodeficiency syndrome (AIDS)/PE-negative group (children who developed clinical category C and without neurologic manifestations) in a cross-sectional study within 12 months before PE or AIDS diagnosis, respectively, the %CD8 ؉ T-lymphocytes were significantly lower in the PE-positive group. Normalized absolute counts of CD8 ؉ T-lymphocytes with respect to seroreverting children were significantly lower in the group of children with encephalopathy with respect to the AIDS/PE-negative group (data not shown). It is interesting that a statistically significant increase was observed in circulating monocyte percentages and absolute counts shortly before the first neurologic symptoms compared with values after PE was established and with those from HIV-1-infected controls. With respect to AIDS-related events, PE was strongly associated with anemia and lymphoid interstitial pneumonitis in the PE-positive group with respect to a group of children with AIDS but w...

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Failure of T-cell homeostasis preceding AIDS in HIV-1 infection

Cited by 225 publications

References 21 publications

Recreational drug use and T lymphocyte subpopulations in HIV-uninfected and HIV-infected men

Recreational drug use and T lymphocyte subpopulations in HIV-uninfected and HIV-infected men

A Tat subunit vaccine confers protective immunity against the immune-modulating activity of the human immunodeficiency virus type-1 Tat protein in mice

Low Blood CD8+ T-Lymphocytes and High Circulating Monocytes Are Predictors of HIV-1-Associated Progressive Encephalopathy in Children

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