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Naive T-cell depletion related to infection by X4 human immunodeficiency virus type 1 in poor immunological responders to highly active antiretroviral therapy.

ABSTRACT: The reasons for poor CD4+ T-cell recovery in some human immunodeficiency virus (HIV)-infected subjects despite effective highly active antiretroviral therapy (HAART) remain unclear. We recently reported that CXCR4-using (X4) HIV-1 could be gradually selected in cellular reservoirs during sustained HAART. Because of the differential expression of HIV-1 coreceptors CCR5 and CXCR4 on distinct T-cell subsets, the residual replication of R5 and X4 viruses could have different impacts on T-cell homeostasis during immune reconstitution on HAART. We examined this hypothesis and the mechanisms of CD4+ T-cell restoration by comparing the virological and immunological features of 15 poor and 15 good immunological responders to HAART. We found a high frequency of X4 viruses in the poor immunological responders. But the levels of intrathymic proliferation of the two groups were similar regardless of whether they were infected by R5 or X4 virus. The frequency of recent thymic emigrants in the poor immunological responders was also similar to that found in the good immunological responders, despite their reduced numbers of naïve CD4+ T cells. Our data, rather, suggest that the naïve T-cell compartment is drained by a high rate of mature naïve cell loss in the periphery due to bystander apoptosis or activation-induced differentiation. X4 viruses could play a role in the depletion of naïve T cells in poor immunological responders to HAART by triggering persistent T-cell activation and bystander apoptosis via gp120-CXCR4 interactions.

SUBMITTER: Delobel P

PROVIDER: S-EPMC1617280 | biostudies-literature | 2006 Oct

REPOSITORIES: biostudies-literature

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Naive T-cell depletion related to infection by X4 human immunodeficiency virus type 1 in poor immunological responders to highly active antiretroviral therapy.

Delobel Pierre P Nugeyre Marie-Thérèse MT Cazabat Michelle M Sandres-Sauné Karine K Pasquier Christophe C Cuzin Lise L Marchou Bruno B Massip Patrice P Cheynier Rémi R Barré-Sinoussi Françoise F Izopet Jacques J Israël Nicole N

Journal of virology 20061001 20

The reasons for poor CD4+ T-cell recovery in some human immunodeficiency virus (HIV)-infected subjects despite effective highly active antiretroviral therapy (HAART) remain unclear. We recently reported that CXCR4-using (X4) HIV-1 could be gradually selected in cellular reservoirs during sustained HAART. Because of the differential expression of HIV-1 coreceptors CCR5 and CXCR4 on distinct T-cell subsets, the residual replication of R5 and X4 viruses could have different impacts on T-cell homeos ...[more]

PMID: 17005700

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Project description:BACKGROUND:The optimal approach to HIV-associated Kaposi sarcoma (HIV-KS) in sub-Saharan Africa is unknown. With large-scale rollout of highly active antiretroviral therapy (HAART) in South Africa, we hypothesized that survival in HIV-KS would improve and administration of chemotherapy in addition to HAART would be feasible and improve KS-specific outcomes. METHODS:We conducted a randomized, controlled, open-label trial with intention-to-treat analysis. Treatment-naive patients from King Edward VIII Hospital, Durban, South Africa, a public-sector tertiary referral center, with HIV-KS, but no symptomatic visceral disease or fungating lesions requiring urgent chemotherapy, were randomized to HAART alone or HAART and chemotherapy (CXT). HAART arm received stavudine, lamivudine, and nevirapine (Triomune; CXT arm received Triomune plus bleomycin, doxorubicin, and vincristine every 3 weeks. When bleomycin, doxorubicin, and vincristine were not available, oral etoposide (50-100 mg for 1-21 days of a 28-day cycle) was substituted. Primary outcome was overall KS response using AIDS Clinical Trial Group criteria 12 months after HAART initiation. Secondary comparisons included time to response, progression-free survival, overall survival, adverse events, HIV control, CD4 reconstitution, adherence, and quality of life. RESULTS:Fifty-nine subjects were randomized to HAART and 53 to CXT; 12-month overall KS response was 39% in the HAART arm and 66% in the CXT arm (difference, 27%; 95% confidence interval, 9%-43%; P = 0.005). At 12 months, 77% were alive (no survival difference between arms; P = 0.49), 82% had HIV viral load <50 copies per milliliter without difference between the arms (P = 0.47); CD4 counts and quality-of-life measures improved in all patients. CONCLUSIONS:HAART with chemotherapy produced higher overall KS response over 12 months, whereas HAART alone provided similar improvement in survival and select measures of morbidity. In Africa, with high prevalence of HIV and human herpes virus-8 and limited resources, HAART alone provides important benefit in patients with HIV-KS.

Project description:BackgroundPeople living with human immunodeficiency virus (HIV) with immuno-virological discordant responses are at an increased risk to develop acquired immunodeficiency syndrome (AIDS) and severe non AIDS events which are risk factors for death. This study was aimed to assess prevalence of immuno- virological discordant responses and associated risk factors among highly active antiretroviral therapy (HAART) users in Tigray, Northern Ethiopia.MethodsA cross sectional study was conducted from September to December 30, 2016 on 260 people living with HIV who started first line HAART from January 2008 to March 2016 at Mekelle hospital and Ayder comprehensive specialized hospital. Baseline and follow-up clinical data and CD4+ result were collected from patient charts. Besides, socio-demographic data and blood samples for CD4 + count and viral load measurement were collected during data collection period. Fisher's exact test, bivariate and multivariate logistic regressions were used for data analysis. P-value < 0.05 with 95% CI was considered as statistically significant.ResultAmong the 260 study participants, 8.80% (95% Confidence Interval (CI) =8.77-8.84%) and 2.70% (95% CI = 2.68-2.72%) had virological and immunological discordant responses, respectively with an overall immuno-virological discordance response of 11.50% (95% CI = 11.46-11.54%). The median age of the study participants at HAART initiation was 35 (IQR: 28-44 years). More than half (58.1%) of the study participants were females. Age at or below 35 years old at HAART initiation (AOR ((95% CI) = 4.25(1.48-12.23), p = 0.007)), male gender ((Adjusted Odds Ratio (AOR) (95% CI) =1.71(1.13-1.10), p = 0.029)), type of regimen given ((AOR(95% CI) = 0.30 (0.10-0.88), p = 0.028)) and good treatment adherence ((AOR (95% CI) = 0.12 (0.030-0.0.48), p = 0.003)) were associated risk factors for virological discordant response. Likewise, immunological discordant response was associated with tuberculosis co-infections (p = 0.016), hepatitis B virus co-infections (p = 0.05) and low CD4+ count (≤100 cells/μl) at baseline (p = 0.026).ConclusionsOver all, immuno-virological discordance response was 11.5% in the study area. Males, low baseline CD4+ count, poor/fair treatment adherence, and TB and HBV co-infections were significantly associated with higher immuno-virological discordance. We recommend that decision of patient treatment outcome, regimen change and patient management response should be done using trends of both viral load and CD4+ count concurrently.

Project description:UnlabelledA number of men receiving prolonged suppressive highly active antiretroviral therapy (HAART) still shed human immunodeficiency virus (HIV) in semen. To investigate whether this seminal shedding may be due to poor drug penetration and/or viral production by long-lived cells within male genital tissues, we analyzed semen and reproductive tissues from macaques chronically infected with simian immunodeficiency virus mac251 (SIVmac251) who were treated for 4 months with HAART, which was intensified over the last 7 weeks with an integrase inhibitor. We showed that a subset of treated animals continued shedding SIV in semen despite efficient HAART. This shedding was not associated with low antiretroviral drug concentrations in semen or in testis, epididymis, seminal vesicles, and prostate. HAART had no significant impact on SIV RNA in the urethra, whereas it drastically reduced SIV RNA levels in the prostate and vas deferens and to a lesser extent in the epididymis and seminal vesicle. The only detectable SIV RNA-positive cells within the male genital tract after HAART were urethral macrophages. SIV DNA levels in genital tissues were not decreased by HAART, suggesting the presence throughout the male genital tract of nonproductively infected cells. In conclusion, our results demonstrate that 4 months of HAART induced variable and limited control of viral infection in the male reproductive organs, particularly in the urethra, and suggest that infected long-lived cells in the male genital tract may be involved in persistent seminal shedding during HAART. These results pave the way for further investigations of male genital organ infection in long-term-treated infected individuals.ImportanceA substantial subset of men receiving prolonged HAART suppressing viral loads in the blood still harbor HIV in semen, and cases of sexual transmission have been reported. To understand the origin of this persistence, we analyzed the semen and male reproductive tissues from SIV-infected macaques treated with HAART. We demonstrated that persistent seminal shedding was not linked to poor drug penetration in semen or semen-producing prostate, seminal vesicle, epididymis, and testis. We revealed that HAART decreased SIV RNA to various extents in all male genital organs, with the exception of the urethra, in which SIV RNA(+) macrophages were observed despite HAART. Importantly, HAART did not impact SIV DNA levels in the male genital organs. These results suggest that infection of male genital organs, and particularly the urethra, could be involved in the release of virus in semen during HAART.

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Naive T-cell depletion related to infection by X4 human immunodeficiency virus type 1 in poor immunological responders to highly active antiretroviral therapy.

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Naive T-cell depletion related to infection by X4 human immunodeficiency virus type 1 in poor immunological responders to highly active antiretroviral therapy.

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