Predictors of Progression in Long-Term Nonprogressors

Ashton, Lesley J.; Carr, Andrew; Cunningham, Philip; Roggensack, Monika; Karen, Mclean; Law, Matthew; Robertson, Mark; Cooper, David A.; Kaldor, John

doi:10.1089/aid.1998.14.117

Cited by 27 publications

(11 citation statements)

References 24 publications

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“…Thus, individuals in LTNP cohorts demonstrated heterogeneous viral loads, and the studies on such cohorts often had conflicting results 1–4. We have recently described a cohort of HIV-1 infected individuals, Natural Viral Suppressors (NVS), who have the ability to naturally suppress HIV-1 to undetectable levels 5. We demonstrated that the NVS had a much lower proviral copy number than controls (including LTNPs), thus confirming our case definition of this cohort.…”

Section: Introductionsupporting

confidence: 74%

“…After informed consent was obtained, NVS patients had to be confirmed HIV-1 positive by Western Blot and proviral DNA, and have demonstrated viral loads <400 copies/ml for a 2 year time period without the use of antiretroviral therapy (one viral load > 400 copies/ml in a 2 year period was allowed), as previously described 5. Patients were recruited from the Institute of Human Virology’s clinics in Baltimore (Evelyn Jordan Center, Baltimore Veterans Administration (VA), and Maryland General Hospital), as well as referrals from other local affiliated clinics.…”

Section: Methodsmentioning

confidence: 99%

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Epidemiologic Characteristics and Natural History of HIV-1 Natural Viral Suppressors

Sajadi

Constantine²,

Mann³

et al. 2009

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Objective The objective of this study was to detail the epidemiologic characteristics and natural history of HIV-1 Natural Viral Suppressors (NVS), a cohort of HIV-1 infected individuals who are able to suppress viral replication to undetectable levels in the absence of therapy. Design and Methods HIV-1 patients who met the NVS criteria were enrolled into a prospective study. The incidence and prevalence of NVS were calculated by performing a chart review on all patients seen in one clinic in a 10 year period. Cumulative probability of progression-free survival was calculated by Kaplan-Meier product limit method. Results Forty individuals enrolled in the study. The median year of diagnosis was 1994, and individuals demonstrated a median 6.7 years of HIV-1 viral suppression and CD4 count of 795 cells/ul. NVS had an incidence of 1.1% (95%CI, 0.0–2.1) and prevalence of 1.5% (95% CI, 0.8–2.1). Only one patient (2.5%) has progressed. Within the first 10 years for follow-up having met the definition of NVS, 95.1% (95% CI 86.5%–100%) of the NVS continued to control their viral loads to undetectable levels. Conclusions The NVS cohort has demonstrated remarkable stability and a low rate of progression over many years. Detailed evaluations of viral-host immune regulatory factors associated with persistent HIV-1 natural viral suppression, as well as loss of such suppression, has the potential to provide important new insight in HIV pathogenesis and future immune regulatory targeted preventive and therapeutic research.

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Section: Introductionsupporting

confidence: 74%

Section: Methodsmentioning

confidence: 99%

Epidemiologic Characteristics and Natural History of HIV-1 Natural Viral Suppressors

Sajadi

Constantine²,

Mann³

et al. 2009

JAIDS Journal of Acquired Immune Deficiency Syndromes

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“…Thus, the joint probabilities of survival up to 7 years and having a CD4 count of >600 might provide a better estimate of LTNP, which was found to be 19.2%. This is substantially higher than the estimated proportions of LTNP reported elsewhere,4,5,23 despite the fact that disease progression rates were found to be high in this Ugandan population 15. It should be noted that the KM methods were used previously to determine survival probabilities in LTNP populations but not to estimate the probability of becoming an LTNP 20.…”

Section: Discussioncontrasting

confidence: 56%

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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“…LTNP samples were obtained from the Australian LTNP cohort that was established in 1994 and is being followed up by the Kirby Institute (formerly the National Centre for HIV Epidemiology and Clinical Research), Sydney, Australia. The LTNPs enrolled in this cohort met the following criteria: asymptomatic HIV-1 disease who had been infected with HIV-1 for at least 8 y prior to study entry and had a CD4 + T cell count $500 cells/ml in the absence of any antiretroviral treatment (12). For this study we excluded LTNPs who had defective virus (nef deletion) or HIV-1 coreceptor polymorphisms (homozygous or heterozygous to the delta 32 CCR5 receptor mutation), which may have explained their LTNP status.…”

Section: Patient Selectionmentioning

confidence: 99%

Differential Regulation of the Let-7 Family of MicroRNAs in CD4+ T Cells Alters IL-10 Expression

Swaminathan

Suzuki²,

Seddiki

et al. 2012

The Journal of Immunology

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140

104

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MicroRNAs (miRNAs) are ∼22-nt small RNAs that are important regulators of mRNA turnover and translation. Recent studies have shown the importance of the miRNA pathway in HIV-1 infection, particularly in maintaining latency. Our initial in vitro studies demonstrated that HIV-1–infected HUT78 cells expressed significantly higher IL-10 levels compared with uninfected cultures. IL-10 plays an important role in the dysregulated cytotoxic T cell response to HIV-1, and in silico algorithms suggested that let-7 miRNAs target IL10 mRNA. In a time course experiment, we demonstrated that let-7 miRNAs fall rapidly following HIV-1 infection in HUT78 cells with concomitant rises in IL-10. To show a direct link between let-7 and IL-10, forced overexpression of let-7 miRNAs resulted in significantly reduced IL-10 levels, whereas inhibition of the function of these miRNAs increased IL-10. To demonstrate the relevance of these results, we focused our attention on CD4+ T cells from uninfected healthy controls, chronic HIV-1–infected patients, and long-term nonprogressors. We characterized miRNA changes in CD4+ T cells from these three groups and demonstrated that let-7 miRNAs were highly expressed in CD4+ T cells from healthy controls and let-7 miRNAs were significantly decreased in chronic HIV-1 infected compared with both healthy controls and long-term nonprogressors. We describe a novel mechanism whereby IL-10 levels can be potentially modulated by changes to let-7 miRNAs. In HIV-1 infection, the decrease in let-7 miRNAs may result in an increase in IL-10 from CD4+ T cells and provide the virus with an important survival advantage by manipulating the host immune response.

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Predictors of Progression in Long-Term Nonprogressors

Cited by 27 publications

References 24 publications

Epidemiologic Characteristics and Natural History of HIV-1 Natural Viral Suppressors

Epidemiologic Characteristics and Natural History of HIV-1 Natural Viral Suppressors

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

Differential Regulation of the Let-7 Family of MicroRNAs in CD4+ T Cells Alters IL-10 Expression

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