Current HIV Research - Volume 10, Issue 7, 2012

During the course of human immunodeficiency virus type 1 (HIV-1) disease, the virus has been shown to effectively escape the immune response with the subsequent establishment of latent viral reservoirs in specific cell populations within the peripheral blood (PB) and associated lymphoid tissues, bone marrow (BM), brain, and potentially other end organs. HIV-1, along with hepatitis B and C viruses (HBV and HCV), are known to share similar routes of transmission, including intravenous drug use, blood transfusions, sexual intercourse, and perinatal exposure. Substance abuse, including the use of opioids and cocaine, is a significant risk factor for exposure to HIV-1 and the development of acquired immune deficiency syndrome, as well as HBV and HCV exposure, infection, and disease. Thus, coinfection with HIV-1 and HBV or HCV is common and may be impacted by chronic substance abuse during the course of disease. HIV- 1 impacts the natural course of HBV and HCV infection by accelerating the progression of HBV/HCV-associated liver disease toward end-stage cirrhosis and quantitative depletion of the CD4+ T-cell compartment. HBV or HCV coinfection with HIV-1 is also associated with increased mortality when compared to either infection alone. This review focuses on the impact of substance abuse and coinfection with HBV and HCV in the PB, BM, and brain on the HIV-1 pathogenic process as it relates to viral pathogenesis, disease progression, and the associated immune response during the course of this complex interplay. The impact of HIV-1 and substance abuse on hepatitis virus-induced disease is also a focal point.

To determine whether CRF07_BC, one of the most predominant strains that accounts for one third HIV-1 prevalence in China, has the ability to infect hematopoietic progenitor cells (HPCs), human Umbilical Cord Blood (UCB) derived CD34+ HPCs isolated with high purity were infected by HIV-1 pseudotyped with CRF07_BC envelope. After HIV-1 infection, ~0.86% CD34+ HPCs were co-stained for CD34 and intracellular HIV Gag. HIV p24 antigen was detectable and reached maximal release between day 2-4 after HIV-1 infection. The data of nested Alu-LTR PCR proved the integration of HIV-1 genome into the host genome occurred in HIV-1-infected HPCs. These data demonstrated that the envelope of CRF07_BC from China has the capability of resulting in infection to CD34+ HPCs, which may serve as a mechanism for long-term latency of HIV-1 infection in vivo.

In a diagnostic laboratory performing analyses for about 40 hospitals and 2,000 physicians treating outpatients results of HIV 4th generation combined antibody/antigen screening assays were monitored over a period of 50 months. In period A (Jan 2007 - Mar 2009) 37,986 serum samples were examined by Architect and in period B (Apr 2009 - Feb 2011) 38,178 samples by Modular system. In period B1 (Apr 2009 - Jun 2010) 24,756 samples were analyzed only by Modular system while in period B2 (July 2010 - February 2011) 13,422 samples were examined in parallel by Modular and Axsym system. Sensitivity and negative predictive value of each was 100%. Specificities ranged from 99.69-99.88% and positive predictive values (ppv) from 35.1-65.9%. Architect test results obtained a better reliability than Modular test results while Axsym test results were similar to that of Architect system. However, specificity and ppv of Modular system was markedly improved in period B2. In summary our study shows that long term monitoring of HIV combined antibody/antigen screening test results allows discovering of impairment and improvement of HIV testing quality. We also show that in a low prevalence region specificities of > 99% are accompanied by relatively low ppv. Increase of cut off values to define reactivity of the tests will increase specificities and ppv without affecting sensitivity.

Immune activation and IL-7/IL7 receptor (CD127) systems are significant for CD4+ T cell defect in AIDS patients. However, the association between immune activation and CD127 expression on T lymphocyte subsets in Chinese pediatric AIDS patients is not well studied. Here, we recruited a cohort of 194 Chinese pediatric AIDS patients: 135 good viral responders (GVRs) and 59 poor viral responders (PVRs). CD38high and HLA-DR+CD8+ T lymphocytes and CD127 expression on T-cell subsets were determined by flow cytometry. Viral load was detected using a quantitative RT-PCR assay. The results showed that pediatric AIDS patients had a lower memory CD4+ percentage and a higher memory CD8+ T-cell percentage. The percentage of naive CD4+T-cells was higher, especially in GVRs. The percentage of CD38high and HLA-DR+CD8+ in PVRs was higher than in GVRs and controls, being positively correlated with viral load and memory CD8+, but negatively correlated with memory CD4+ T cells. The percentage of CD127+ memory CD4+ T cells in GVRs was higher than in PVRs, but lower than in controls. CD127 expression was positively correlated with percentage of CD4+ subsets and naive CD8+ T cells, but negatively correlated with percentage of memory CD8+ T cells. Our study demonstrates that the percentages of CD38high and HLA-DR+ CD8+ T cells are good markers to evaluate immune activation of pediatric AIDS patients, and elevated immune activation has a more profound effect on memory T cells. IL- 7/CD127 system is more important to maintain the proportion of naive T cells.

In patients receiving highly active antiretroviral therapy (HAART), increase of naive T-cell production, as measured by T-cell receptor rearrangement excision circles (TRECs), is an indicator of immune reconstitution. Our objective was to assess whether treating opportunistic infections (OIs) prior to HAART initiation affects CD4 T-cells recovery and TRECs in patients on HAART. HIV-infected patients presenting no OIs or treated OIs were prospectively enrolled prior to HAART initiation and followed-up over 12 months of HAART. CD4 T-cells and TRECs were measured at baseline, 6 and 12 months HAART and compared between patients presenting no OIs and those with treated OIs. Univariate and multivariate logistic regression models were used to identify potential factors associated with low TREC increase after 12 months HAART. Forty-four HIV-infected patients, 31 presenting no OIs and 13 with treated OIs at HAART initiation were enrolled. Patients presenting no OIs tended to have higher CD4 T-cell gain than those with treated OIs (151 vs 89 cells/μL; p = 0.05) after 6 months HAART but not after 12 months HAART (120 vs 149 cells/μL; p = 0.84). Among patients presenting no OIs, TREC levels significantly increased from baseline through 12 months HAART while among those with treated OIs, there was a trend for increase only after 12 months. Our study indicates that treatment of OIs prior to HAART does not lead to impaired CD4 T-cells recovery and thymic outputs.

Background: We aimed to assess the impact of TDF/FTC +LPV/r-based HAART on the quality of immune reconstitution and on microbial translocation (MT) in HIV-infected antiretroviral-naïve late presenting patients. Methods: 40 HIV+ antiretroviral-naive patients starting a first TDF/FTC+LPV/r HAART with CD4+≤350 cell/μL (20 “severe immune depression” patients -SID CD4+≤100/μL; 20 “moderate immune depression” patients –MID, CD4+ 200- 350/μL) were followed for 12 months (T12). CD38+CD8+, CD45R0+CD38+CD8+, CD95+CD4+/CD8+, CD127+CD4+/CD8+, pStat5 signalling (flow cytometry), plasma IL-7, sCD14 (ELISA), LPS (LAL) were tested at T0 and T12. Results: By T12, both study groups displayed significant CD4+ increase and HIV-RNA reduction (p<.01). Despite similar CD38+CD8+ reduction in both SID (p=.039) and MID (p=.007), SID displayed a significant rise in CD45R0+CD38+CD8+ (p=.039). MID displayed significant increase of CD95+CD4+ (p=.002), with higher baseline and T12 levels (p=.024; p=.002), suggesting reduced commitment to apoptosis. At T12, different IL-7/IL-7R profile was shown according to pre-therapy immune depression. As compared to SID, MID increased circulating IL-7 (p=.049) displaying higher baseline and T12 CD127+CD4+ (p=.0001; p=.004) and CD127+CD8+ (p=.006; p=.009). By T12, only MID displayed significant reduction in LPS (p=.020) and sCD14 (p=.005). Conclusions: In antiretroviral-naive late presenters, we show different immune reconstitution quality and MT upon 12 months TDF/FTC+LPV/r-containing HAART according to the severity of pre-therapy immune depression. Despite equal T-cell activation decline, only MID patients tend to reduce pro-apoptotic T-lymphocytes, with a gain in circulating IL-7 and higher CD127+ central-memory T-cells, and a possible control over MT.

No data are available on the long-term immunovirological outcome of HIV-positive pregnant women experiencing sub–therapeutic antiretroviral drug (ARV) concentrations during pregnancy. The objective of our study was to assess the long-term virological outcome in pregnant women treated with HAART. A prospective, multi-center study enrolled 60 HIV-infected pregnant women stratified into 3 groups according to the response to HAART. Group A, women successfully treated with HAART; Group B, women with confirmed virological failure during HAART; Group C, women successfully treated with HAART during pregnancy for prevention of vertical transmission only. Smoking, alcohol use, low adherence to therapy, and increased viral load at delivery were significantly associated to virological failure at univariate analysis. At multivariate regression analysis, only adherence to therapy was reported as an independent variable related to the virological response (p <0.001). Virological failure during follow-up was reported in 2 (25.0%) of the 8 women with sub therapeutic Ctrough and in 4 of the 33 (12.1%) women with therapeutic Ctrough (p=0.33). In group C, the viro-immunological set points during follow-up did not differ from those observed before HAART initiation. No significantly increased rate of virological failure after delivery was reported in women with sub-therapeutic ARV concentrations during pregnancy and long-term follow-up. The long-term virological outcome was independently associated to reduced adherence to therapy. Evaluation of the clinical impact of the low plasma ARV concentrations during pregnancy on the long-term virological outcome deserves further larger studies.

Introduction: Human Papillomavirus infections have been shown to be crucial for the development of cervical intraepithelial neoplasia and subsequent cervical cancer. The aim of this study is to describe the prevalence of different genotypes of HPV, in a population of HIV-positive women, compared to the negative ones, and their oncogenic risk. Patients and Method: A case-control study comparing HPV genotype distribution between 93 HIV-seropositive and 186 HIV-seronegative women, matched for age and severity of cervical lesions, who attending colposcopic service of our departments for periodical Pap smear and HPV DNA full genotyping by SPF-10 LiPA assay. Results: No significant difference was found in genotype distribution between HIV positive and HIV negative women. Only the prevalence of HPV56 was higher in HIV positive women (p=0,046). The rates of HPV 6, 11, 16 and 18 were similar in both groups. The likelihood of the detection of three or more HPV genotypes was significantly associated with CIN (OR=2.0; 95% CI=1.1–3.8; p= 0.026) but only marginally to HIV-positive serostatus (OR=1.68; 95% CI=0.89–3.16; p= 0.1). High grade cervical lesions are associated with high risk viruses like HPV 16 and 18 and with multiple cervical HPV infections. Conclusions: The tendency to treat HIV disease with high active antiretroviral therapy may reduce the impact of immunosuppression and make the course of such HPV infections more similar to that among women who are not HIVinfected. As in immunocompetent women, high oncogenic risk viral type and multiple infections are associated with a histologically proven cervical intraepithelial lesions.

Background: Central nervous system infections caused by Cryptococcus neoformans remain to be opportunistic infections with high mortality in severely immunocompromised patients such as patients with AIDS. Amphotericin B deoxycholate and fluconazole remain to be the drugs of choice; however, in consideration of the intolerance to amphotericin B deoxycholate and the possible resistance to fluconazole, it is necessary to evaluate other azoles, such as posaconazole, that have demonstrated lower adverse events. The objective of this study was to describe the characteristics and clinical and microbiological response of the use of posaconazole in patients with CNS infections caused by C. neoformans. Methods: We designed a case study that included eight patients diagnosed with AIDS and cryptococcal meningitis. Seven patients were treated with 800 mg of posaconazole orally for 28 days. Results: During the second week of treatment, a cerebrospinal fluid (CSF) culture was performed and was negative for the development of C. neoformans. The patients showed an improvement in signs and symptoms of impairment of the CNS such as reduction of cephalea, fever, visual disturbances such as double vision, meningism and papilledema, and improved alertness and environmental awareness. Conclusions: CNS fungal infections usually occur in immunocompromised patients. The use of systemic antifungal agents contributes to the development of fungal resistance. The results of this study suggest that posaconazole is a good alternative in the treatment of fungal CNS infection due to C. neoformans.