Accelerate HIV Disease Progression Research Articles

Effects of HCV on Basal and Tat-Induced HIV LTR Activation

Hepatitis C virus (HCV) co-infection occurs in ∼30–40% of the HIV-infected population in the US. While a significant body of research suggests an adverse effect of HIV on HCV replication and disease progression, the impact of HCV on HIV infection has not been well studied. Increasing data suggest that hepatocytes and other liver cell populations can serve as reservoirs for HIV replication. Therefore, to gain insight into the impact of HCV on HIV, the effects of the HCV Core protein and infectious hepatitis C virions were evaluated on basal and Tat-induced activation of the HIV long terminal repeat (LTR) in hepatocytes. The HIV LTR was highly induced by the HIV transactivator protein Tat in hepatocytes. Activation varied according to the number of NF-kB binding sites present in the LTRs from different HIV subtypes. Involvement of the NF-kB binding pathway in LTR activation was demonstrated using an NF-kB inhibitor and deletion of the NF-kB binding sites. TNFα, a pro-inflammatory cytokine that plays an important role in HIV pathogenesis, also induced LTR activity in hepatocytes. However, HIV LTR activity was suppressed in hepatocytes in the presence of HCV Core protein, and the suppressive effect persisted in the presence of TNFα. In contrast, infectious hepatitis C virions upregulated HIV LTR activation and gene transcription. Core-mediated suppression remained unaltered in the presence of HCV NS3/4A protein, suggesting the involvement of other viral/cellular factors. These findings have significant clinical implications as they imply that HCV could accelerate HIV disease progression in HIV/HCV co-infected patients. Such analyses are important to elucidate the mechanisms by which these viruses interact and could facilitate the development of more effective therapies to treat HIV/HCV co-infection.

The Pervasive Effects of Childhood Sexual Abuse

The Pervasive Effects of Childhood Sexual Abuse

Examining the Relationship between Urogenital Schistosomiasis and HIV Infection

BackgroundUrogenital schistosomiasis, caused by infection with Schistosoma haematobium, is widespread and causes substantial morbidity on the African continent. The infection has been suggested as an unrecognized risk factor for incident HIV infection. Current guidelines recommend preventive chemotherapy, using praziquantel as a public health tool, to avert morbidity due to schistosomiasis. In individuals of reproductive age, urogenital schistosomiasis remains highly prevalent and, likely, underdiagnosed. This comprehensive literature review was undertaken to examine the evidence for a cause-effect relationship between urogenital schistosomiasis and HIV/AIDS. The review aims to support discussions of urogenital schistosomiasis as a neglected yet urgent public health challenge.Methodology/Principal FindingsWe conducted a systematic search of the literature including online databases, clinical guidelines, and current medical textbooks. We describe plausible local and systemic mechanisms by which Schistosoma haematobium infection could increase the risk of HIV acquisition in both women and men. We also detail the effects of S. haematobium infection on the progression and transmissibility of HIV in co-infected individuals. We briefly summarize available evidence on the immunomodulatory effects of chronic schistosomiasis and the implications this might have for populations at high risk of both schistosomiasis and HIV.Conclusions/SignificanceStudies support the hypothesis that urogenital schistosomiasis in women and men constitutes a significant risk factor for HIV acquisition due both to local genital tract and global immunological effects. In those who become HIV-infected, schistosomal co-infection may accelerate HIV disease progression and facilitate viral transmission to sexual partners. Establishing effective prevention strategies using praziquantel, including better definition of treatment age, duration, and frequency of treatment for urogenital schistosomiasis, is an important public health priority. Our findings call attention to this pressing yet neglected public health issue and the potential added benefit of scaling up coverage of schistosomal treatment for populations in whom HIV infection is prevalent.

Cocaine reduces thymic endocrine function: another mechanism for accelerated HIV disease progression.

Thymulin is a thymic peptide important for the maturation and differentiation of immature thymocytes, which have been found to be depressed in patients with low-level CD4(+) cell recovery despite viral control. Substance use is associated with faster progression of HIV disease, which has been ascribed to poor adherence to antiretroviral medication. Recent findings of an association between cocaine use and decline in CD4(+) cell counts independent of antiretroviral adherence indicate alternative mechanisms for disease progression. We evaluated the relationship between thymulin activity, CD4(+) and CD8(+) cell counts and the CD4(+)/CD8(+) ratio, and the covariate effects of substance use cross-sectionally in 80 HIV(+) active substance users and over 12 months in 40 participants. Thymulin activity was analyzed in plasma using a modification of the sheep rosette bioassay. Thymulin activity was negatively associated with cocaine use (β = -0.908,95% CI: -1.704, -0.112; p = 0.026). Compared to those who do not use cocaine, cocaine users were 37% less likely to have detectable thymulin activity (RR = 0.634, 95% CI: 0.406, 0.989 p = 0.045) and were 75 times more likely to show a decrease in thymulin activity (OR = 74.7, 95% CI: 1.59, 3519.74; p = 0.028) over time. CD4(+) cell count was positively associated with thymulin activity (β = 0.127, 95% CI: 0.048,0.205; p = 0.002), detectable thymulin activity was 2.32 times more likely in those with a CD4 cell count ≥200 cells/μl (RR = 2.324, 95% CI: 1.196, 4.513, p = 0.013), and those with an increase in CD4 cell counts were more likely to show an increase in thymulin activity (OR = 1.02, 95% CI: 1.00, 1.034; p = 0.041) over time. Thymulin activity is predictive of HIV disease progression and is depressed in cocaine users independent of antiretroviral treatment (ART) and HIV viral load. Understanding the mechanisms for accelerated HIV disease progression provides opportunities to find alternative strategies to counteract immunosuppression.

Sustained CD28 Expression Delays Multiple Features of Replicative Senescence in Human CD8 T Lymphocytes

CD28 costimulatory signal transduction in T lymphocytes is essential for optimal telomerase activity, stabilization of cytokine mRNAs, and glucose metabolism. During aging and chronic infection with HIV-1, there are increased proportions of CD8 T lymphocytes that lack CD28 expression and show additional features of replicative senescence. Moreover, the abundance of these cells correlates with decreased vaccine responsiveness, early mortality in the very old, and accelerated HIV disease progression. Here, we show that sustained expression of CD28, via gene transduction, retards the process of replicative senescence, as evidenced by enhanced telomerase activity, increased overall proliferative potential, and reduced secretion of pro-inflammatory cytokines. Nevertheless, the transduced cultures eventually do reach senescence, which is associated with increased CTLA-4 gene expression and a loss of CD28 cell surface expression. These findings further elucidate the central role of CD28 in the replicative senescence program, and may ultimately lead to novel therapies for diseases associated with replicative senescence.

Alcohol Use Accelerates HIV Disease Progression

The effects of alcohol abuse on HIV disease progression have not been definitively established. A prospective, 30-month, longitudinal study of 231 HIV(+) adults included history of alcohol and illicit drug use, adherence to antiretroviral therapy (ART), CD4(+) cell count, and HIV viral load every 6 months. Frequent alcohol users (two or more drinks daily) were 2.91 times (95% CI: 1.23-6.85, p = 0.015) more likely to present a decline of CD4 to <or=200 cells/microl, independent of baseline CD4(+) cell count and HIV viral load, antiretroviral use over time, time since HIV diagnosis, age, and gender. Frequent alcohol users who were not on ART also increased their risk for CD4 cell decline to <or=200 cells/mm(3) (HR = 7.76: 95% CI: 1.2-49.2, p = 0.03). Combined frequent alcohol use with crack-cocaine showed a significant risk of CD4(+) cell decline (HR = 3.57: 95% CI: 1.24-10.31, p = 0.018). Frequent alcohol intake was associated with higher viral load over time (beta = 0.259, p = 0.038). This significance was maintained in those receiving ART (beta = 0.384, p = 0.0457), but not in those without ART. Frequent alcohol intake and the combination of frequent alcohol and crack-cocaine accelerate HIV disease progression. The effect of alcohol on CD4(+) cell decline appears to be independent of ART, through a direct action on CD4 cells, although alcohol and substance abuse may lead to unmeasured behaviors that promote HIV disease progression. The effect of alcohol abuse on viral load, however, appears to be through reduced adherence to ART.

Hormonal contraception and HIV disease progression: a multicountry cohort analysis of the MTCT-Plus Initiative.

HIV-infected women need access to safe and effective contraception. Recent animal and human data suggest that hormonal contraception may accelerate HIV disease progression. We compared the incidence of HIV disease progression among antiretroviral therapy-naive women with and without exposure to hormonal contraception at 13 sites in Africa and Asia. Disease progression was defined as becoming eligible for antiretroviral therapy or death. Between 1 August 2002 and 31 December 2007, the MTCT-Plus programs enrolled 7846 women. In total, 4109 (52%) women met eligibility criteria for this analysis and contributed 5911 person-years of follow-up (median follow-up, 379 days; interquartile range, 121-833). At baseline, 3064 (75%) women reported using either no contraception or a nonhormonal method, whereas 823 (20%) reported using implants/injectables and 222 (5%) reported using oral contraceptive pills. The disease progression outcome was met by 944 (29%) women (rate, 18.3/100 woman-years). Neither implants/injectables (adjusted hazard ratio 1.0, 95% confidence interval 0.8-1.1) nor oral contraceptive pills (adjusted hazard ratio 0.8, 95% confidence interval 0.6-1.1) were associated with disease progression. Treating contraceptive method as a time-varying exposure did not change this negative finding. This multicountry cohort analysis provides some reassurance that hormonal contraception is not associated with HIV disease progression. Further research is needed to address the contraceptive needs of HIV-infected women.

The effect of post-traumatic stress disorder on HIV disease progression following hurricane Katrina

Post-traumatic stress disorder (PTSD) is a common psychological outcome of any disaster. The purpose of this study was to examine the effects of PTSD on disease progression among HIV-infected persons in metropolitan New Orleans post-hurricane Katrina. One-year post-storm, a convenience sample of 145 HIV-infected patients who returned to care at the HIV Outpatient Program clinic in New Orleans were interviewed. Clinical factors pre and one and two years post-disaster were abstracted from medical records and compared by PTSD status. Of the 145 participants, 37.2% had PTSD. Those with PTSD were more likely than those without PTSD to have detectable plasma viral loads at both follow-up time points post-disaster and more likely to have CD4 cell counts <200/mm3 two years post-disaster. They were also more likely to have had medication interruptions immediately post-disaster. Our findings corroborate the findings of others that PTSD accelerates HIV disease progression. Disaster planners should consider the special counseling and medication safeguards needs of HIV-infected persons.

Crack-Cocaine Use Accelerates HIV Disease Progression in a Cohort of HIV-Positive Drug Users

HIV infection is prevalent among substance abusers. The effects of specific illicit drugs on HIV disease progression have not been established. We evaluated the relationship between substances of abuse and HIV disease progression in a cohort of HIV-1-positive active drug users. A prospective, 30-month, longitudinal study was conducted on 222 HIV-1 seropositive drug users in Miami, FL. History of illicit drug, alcohol, and medication use, CD4+ cell count, and viral load were performed every 6 months. Crack-cocaine users were 2.14 times [95% confidence interval (CI): 1.08 to 4.25, P = 0.029] more likely to present a decline of CD4 to <or=200 cells/mL, independent of antiretroviral use. Viral load over 30 months was significantly higher in crack users (beta = 0.315, P = 0.037) independent of highly active antiretroviral therapy (HAART) over time. The only multidrug combination that significantly increased the risk of disease progression was crack cocaine with marijuana (hazard ratio = 2.42; 95% CI: 1.042 to 5.617, P = 0.04). Of those on HAART, a significantly lower proportion of crack-cocaine users versus nonusers had controlled viral load (P < 0.001), suggesting lower medication adherence, whereas crack-cocaine users not on HAART showed a greater risk for HIV disease progression than nonusers (hazard ratio = 3.946; 95% CI: 1.049 to 14.85, P = 0.042). Crack-cocaine use facilitates HIV disease progression by reducing adherence in those on HAART and by accelerating disease progression independently of HAART.

Immune reconstitution inflammatory syndrome

Immune reconstitution inflammatory syndrome (IRIS) is a paradoxical deterioration in clinical status in a patient on antiretroviral treatment (ART) despite satisfactory control of viral replication and improvement of CD4 count. To study development of IRIS as a part of ART. Hundred patients on antiretroviral treatment were studied prospectively in the Department of Skin and VD over a period of 2 years. Patients were asked to come if they developed any symptoms or on a monthly basis. They were screened clinically and investigated suitably for evidence of opportunistic infections. Out of 100 patients, 10 patients did not come for follow-up. Twenty (22.2%) out of the 90 patients developed IRIS. Herpes zoster (HZ), herpes simplex virus (HSV), and tuberculosis (TB) were the cases of IRIS seen in the present study. IRIS in terms of HSV/TB is known to accelerate HIV disease progression. Hence early detection and prompt treatment, along with continuation of highly active ART, are of utmost importance.

Below the belt: new insights into potential complications of HIV-1/schistosome coinfections

Areas of the world with high endemnicity for helminth parasites overlap with those regions that have a seemingly disproportionate prevalence of HIV/AIDS. This has fueled speculation that potential pathological interactions between these infectious agents may accelerate disease progression. The proximity of many helminth infections to gastrointestinal mucosal sites combined with the recent discovery that acute HIV-1 infection causes early and massive depletion of CD4+ T cells in the gut furthers the potential pathological significance of co-infection. In this review, the 'gut wrenching' consequences of schistosome infection on HIV disease progression that may ensue during coinfection are considered. Massive depletion of CD4+ T cells in the gut during acute HIV-1 infection suggests that in addition to the administration of highly active antiretroviral therapy, limiting viral infection of susceptible cells in the gut after initial exposure may offer the best opportunity for slowing disease progression. In addition to memory T cells, mast cells, which are present in the intestinal lamina propria and upregulated in the gut during schistosome infection, have been recently described as an inducible reservoir of persistent HIV-1 infection. Schistosome infections create immune environments that may accelerate HIV disease progression. Their impact on highly active antiretroviral therapy should be considered.

Iron Status Is an Important Cause of Anemia in HIV-Infected Tanzanian Women but Is Not Related to Accelerated HIV Disease Progression ,

In HIV-infected populations from developing countries, it is unclear what proportion of anemia is attributable to iron deficiency (ID) and whether high body iron stores worsen HIV disease progression. We therefore evaluated these research questions in 584 HIV-infected Tanzanian women. Hemoglobin (Hb), serum ferritin (SF), serum transferrin receptor (sTfR), and C-reactive protein (CRP) concentrations were evaluated between 13 and 43 wk after women gave birth. ID was defined as SF or sTfR outside normal ranges, and ID anemia (IDA) as ID plus low Hb. In multivariate Cox regression models, the association between SF and HIV disease progression was assessed. Participants received iron + folate supplements during pregnancy. Hb (r = −0.159; P = 0.0001), SF (r = 0.355; P < 0.0001), and sTfR/log SF index (r = −0.119; P = 0.004) were related to CRP, whereas sTfR (r = 0.029; P = 0.48) was not. Prevalence estimates were 39.7% for ID and 23.6% for IDA. ID was associated with 48.9% of anemia cases. Categories of SF were not significantly associated with HIV-related mortality or progression to stage 4. Nevertheless, SF > 150.0 μg/L was related to a nonsignificantly elevated risk of progression to stage 4 (rate ratio = 1.78; 95% CI = 0.68–4.64; P = 0.24) compared with SF < 12.0 μg/L. In HIV-infected, parous women from sub-Saharan Africa, ID is of moderately high prevalence and is an important underlying cause of anemia. High storage iron does not appear to be related to HIV disease progression in this population, but more research on the role of iron during HIV disease is needed.

Selenium Status Is Associated with Accelerated HIV Disease Progression among HIV-1–Infected Pregnant Women in Tanzania

Selenium deficiency has been implicated in accelerated disease progression and poorer survival among populations infected with HIV in developed countries, yet these associations remain unexamined in developing countries. Among 949 HIV-1-infected Tanzanian women who were pregnant, we prospectively examined the association between plasma selenium levels and survival and CD4 counts over time. Over the 5.7-y median follow-up time, 306 of 949 women died. In a Cox multivariate model, lower plasma selenium levels were significantly associated with an increased risk of mortality (P-value, test for trend = 0.01). Each 0.1 micromol/L increase in plasma selenium levels was related to a 5% (95% CI = 0%-9%) decreased risk of mortality. Plasma selenium levels were not associated with time to progression to CD4 cell count < 200 cells/mm(3) but were weakly and positively related to CD4 cell count in the first years of follow up. Selenium status may be important for clinical outcomes related to HIV disease in sub-Saharan Africa.

Mannoproteins of Cryptococcus neoformans induce proliferative response in human peripheral blood mononuclear cells (PBMC) and enhance HIV-1 replication.

To investigate the possible role of Cryptococcus neoformans var. neoformans in HIV disease progression, and to identify the responsible cryptococcal components, an in vitro cell culture model was set up to study the C. neoformans-induced enhancement of HIV replication in HIV-1-infected PBMC. Similar to whole C. neoformans, cell-wall membrane fraction and mannoproteins induced proliferation of PBMC and enhancement of lymphotropic HIV replication in HIV-infected PBMC, while galactoxylomannan did not. MoAbs capable of interfering with MHC class II-mediated antigen presentation prevented the induction of cell proliferation by whole C. neoformans or cryptococcal mannoproteins. MoAb binding to adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1) also inhibited C. neoformans-induced cell proliferation. In addition, anti-MHC class II MoAb inhibited the enhancement of HIV replication by C. neoformans. The results suggest that: (i) C. neoformans may accelerate HIV disease progression by stimulation of HIV replication through MHC class II-mediated antigen presentation; and (ii) cryptococcal mannoprotein may be one of the responsible components. The ability to enhance HIV replication in PBMC in vitro is not unique for C. neoformans. However, this is the first report to study in detail a yeast-induced enhancement of HIV replication in PBMC.

Issues in the treatment of Mycobacterium tuberculosis in patients with human immunodeficiency virus infection.

The HIV/AIDS pandemic has led to a rise in the incidence of tuberculosis and an epidemic of co-infection in many developing countries. Treatment of Mycobacterium tuberculosis in persons with HIV infection presents several challenges to the clinician particularly in resource-poor countries. As will be discussed in this paper diagnosis of latent tuberculosis relies on tuberculin skin testing which has poor sensitivity and reproducibility in immunocompromised patients. The World Health Organization (WHO) recommends treatment of active tuberculosis as the primary means of global tuberculosis control. In practice treatment of active tuberculosis typically requires that a symptomatic patient self-report to a health service for evaluation and management. Even if this approach to tuberculosis control were sufficient many logistic and clinical problems remain involving tuberculosis diagnosis and therapy in the patient with HIV/AIDS. Recognizing the significant clinical and public health challenges surrounding the treatment of tuberculosis in patients with HIV infection this paper will address a number of issues relevant to the care of co-infected patients. These include current guidelines for the treatment of active tuberculosis as well as the diagnosis and treatment of latent tuberculosis in HIV-positive patients. The paper concludes with a discussion of promising new drugs for tuberculosis treatment. (excerpt)

Genetic polymorphism in CX3CR1 and risk of HIV disease.

Faure et al . ([1][1]) reported that allele M280 of the chemokine receptor/HIV coreceptor CX3CR1 is associated with both increased risk of HIV infection and accelerated HIV disease progression in studies of Caucasian HIV cohorts from France. In the seroconverters (SEROCO) cohort, the relative risk (

Valproic acid may accelerate HIV disease progression

Valproic acid may accelerate HIV disease progression

Coinfection with HTLV-I and HIV: increase in HTLV-I-related outcomes but not accelerated HIV disease progression?

Human T-lymphotropic virus type I (HTLV-I) and HTLV-II have been postulated to accelerate disease progression in patients coinfected with HIV. However, recent evidence suggests that HTLV-II has no effect on HIV disease progression. In addition, it has recently been reported that HIV viral load was not increased in subjects coinfected with HTLV-I, suggesting that the biologic basis for the hypothesis does not exist. Several recent studies in Brazil, however, suggest that coinfection with HTLV-I and HIV has substantial medical consequences. For example, coinfection was associated with a higher CD4 lymphocytes count following adjustment for HIV viral load or HIV clinical stage. In addition, coinfected subjects have a high prevalence of clinical significant myelopathy. The effect of other putative viruses as cofactors in HIV disease progression is also discussed.