Current HIV Research (v.10, #3)

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Bacterial vaginosis (BV) and Trichomonas vaginalis (TV) infections are both very common and are associated with increased risk of sexual transmission of HIV. There are several mechanisms by which BV and TV could affect susceptibility including inducing pro-inflammatory cytokines and disrupting mucosal barrier function. This review highlights recent advances in our understanding of how these genital conditions lead to an increased risk of HIV infection in women.

Neisseria gonorrhoeae (GC), a major cause of pelvic inflammatory disease, can facilitate HIV transmission. In response to GC infection, genital epithelial cells can produce cytokines, chemokines and defensins to modulate HIV infection and infectivity. GC can also induce the production of cytokines and chemokines in monocytes and modulate T cell activation. In vivo, an increase in the number of endocervical CD4+ T cells has been found in GC-infected women. Additionally, GC appears to modulate HIV-specific immune responses in HIV-exposed sex workers. Interestingly, in vitro, GC exhibits HIV enhancing or inhibitory effects depending on the HIV target cells. This review summarizes molecular and immunological aspects of the modulation of HIV infection and transmission by GC. Future studies using a multi-cellular system or in animal models will offer insight into the mechanisms by which GC increases HIV transmission.

Among the now pandemic sexually transmitted infections (STIs), Chlamydia trachomatis (C. trachomatis) is the predominant bacterial pathogen and human immunodeficiency virus type 1 (HIV-1) is the most lethal of the viral pathogens. The female genital tract is the primary site for heterosexual transmission of both C. trachomatis and HIV-1. Infection with C. trachomatis, and with a variety of other STIs, increases the risk for transmission of HIV-1, although the mechanisms for this finding remain unclear. We have used in vitro modeling to assess the mechanisms by which infection with genital C. trachomatis serovars might increase the transmission of HIV-1 across the female genital tract. C. trachomatis infection of an immortalized endocervical epithelial cell line (A2EN) increases the cell surface expression of the HIV-1 alternative primary receptor, galactosyl ceramide (GalCer), and of the HIV-1 co-receptors, CXCR4 and CCR5. C. trachomatis infection also increases the binding of HIV-1 to A2EN cells, and, subsequently, increases levels of virus in co-cultures of HIV-exposed A2EN and susceptible MT4-R5 T cells. Finally, in vivo endocervical cell sampling reveals a dramatic increase in the number of CD4+, CXCR4 and/or CCR5 positive T cell targets in the endocervix of C. trachomatis positive women when compared to those who are C. trachomatis negative. This combination of in vitro and in vivo results suggests several mechanisms for increased transmission of HIV-1 across the endocervices of C. trachomatis-infected women.

Over the last thirty years, epidemiologic and molecular studies indicate a strong and synergist relationship between the dual epidemics of herpes simplex type 2 (HSV-2) and HIV-1 infection. While prospective studies show that HSV-2 infection increases the risk for HIV-1 acquisition by 2- to 3-fold, HSV-2 suppression with standard prophylactic doses of HSV-2 therapy did not prevent HIV-1 acquisition. Reconciling these discrepancies requires understanding recent HSV-2 pathogenesis research, which indicates HSV-2 infection is not a latent infection with infrequent recurrence but a near constant state of reactivation and viral shedding which is not completely suppressed by standard antivirals. Because current antivirals do not prevent or fully suppress HSV-2 replication, priorities are HSV-2 vaccine development and antivirals that reach high concentrations in the genital mucosa and suppress the persistent genital inflammation associated with genital herpes reactivation in order to reduce the increased susceptibility to HIV-1 infection associated with HSV-2. HIV-1 and HSV-2 synergy is also seen among co-infected individuals who exhibit higher HIV-1 viral load compared to HSV-2 uninfected individuals. Standard HSV-2 therapy modestly lowers HIV-1 viral load and is associated with slower HIV-1 disease progression. A promising area of research is higher doses of HSV-2 suppressive therapy achieving a greater reduction in plasma HIV-1 RNA, which could translate to greater reductions in HIV-1 disease progression and infectiousness. However, many questions remain to be answered including potential effectiveness and cost-effectiveness of higher dose HSV-2 suppressive therapy. Mathematical models of HSV-2 and HIV-1 at a population level would be useful tools to estimate the potential impact and cost-effectiveness of higher dose HSV-2 suppressive therapy.

A wide variety of infections, including bacteria, viruses, fungi and protozoa occur in the immunocompromised condition associated with human immunodeficiency virus type 1 (HIV-1) infection and acquired immunodeficiency syndrome (AIDS). Although these opportunistic infections are believed to arise as an effect of the immunodeficiency, these microbes sometimes promote the disease progression of HIV-1 infection by enhancing viral replication or modulating host immune responses. Here we review the experimental and clinical evidence supporting such causal relationships associated with periodontogenic bacteria. Periodontal disease, caused by subgingival infection with oral anaerobic bacteria, typically Porphyromonas gingivalis (P. gingivalis) belonging to the phylum Bacteroidetes, is found worldwide and is one of the most prevalent microbial diseases of mankind. Emerging evidence implicates the involvement of P. gingivalis infection in the progression of HIV-1 infection. We demonstrate that P. gingivalis can induce HIV-1 reactivation via chromatin modification, and that the bacterial metabolite butyric acid produced in anaerobic conditions is responsible for this effect. These findings suggest that periodontal diseases could act as a risk factor for HIV-1 reactivation in infected individuals and might contribute to AIDS progression. Furthermore, it would imply that prevention and early treatment of periodontitis involving P. gingivalis infection could effectively block further clinical progression of AIDS.

Objectives: To determine the anemia prevalence and the correlation between complete blood count (CBC) analysis and renal function parameters in HIV-1-infected population. Methods: It was a single-center study set in Warsaw (Poland) over a 3-year period. The study was performed in 214 adult HIV-1- infected patients (180 males and 34 females, aged from 20 to 69 years old, mean age 39.55 years, 130 on combined antiretroviral therapy, cART). Glomerular filtration rate (GFR) was estimated using the re-expressed Modification of Diet in Renal Disease (MDRD) and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas. In statistical analyses U Mann-Whitney and Spearman correlation test as logistic regression analysis was used. Results: 25.2% of studied patients were anemic. In all of them, estimated GFR (eGFR) was positively correlated with red blood cells (RBC) and platelet (PLT) count, and negatively correlated with mean corpuscular volume (MCV) and mean corpuscular hemoglobin concentration (MCHC). All these correlations were statistically significant (p < 0.001) and independent of gender and used type of eGFR formula. In logistic regression analysis, lower eGFR strongly predicted lower RBC and PLT levels (p < 0.0001; OR 0.08, 95%CI: 0.03, 0.22 and OR 0.99, 95%CI: 0.987, 0.993, respectively). Conclusions: Our findings suggest a strong association between CBC and renal function in ARV-treated HIV-infected patients who fulfilled the criteria of anemia. Consequently, eGFR in all HIV-infected subjects with anemia, especially on treatment with nephrotoxic drugs and concomitant thrombocytopenia, should be monitored more frequently then standardly recommended every 3-6 months.

HIV-infected individuals have excess rates of invasive pneumococcal disease. We investigated risk factors for nasopharyngeal pneumococcal colonization at baseline and after 9 months in 96 HIV patients immunized twice with 7- valent pneumococcal conjugate vaccine ±1mg CPG 7909. In total, 22 patients (23%) were colonized, 11 at baseline only, four at both baseline and 9 months, and seven at 9 months only. Compared to non-colonized patients, more colonized patients were smokers, had lower CD4+ nadir and had an AIDS-diagnosis. Immunization, antiretroviral treatment and the CPG adjuvant had no impact on colonization. These results suggest preventive strategies in addition to pneumococcal immunization.

Background: The disease profile of treatment-experienced HIV-1 patients (TEPs) looks different today compared with that of 5 years ago. Because less highly treated DUET patients may more closely resemble today's TEPs, we conducted a post hoc efficacy and safety analysis of the pooled 96-week DUET data stratified by level of treatment experience. Methods: TEPs with HIV-1 were randomised to etravirine (ETR) 200mg twice daily (bid) or placebo bid with a background regimen for 48 weeks (plus optional 48-week extension). TEPs were categorized using 10 demographic and disease characteristics that in prior studies of treatment-experienced subjects had been associated with virologic response; patients meeting ≥5 criteria were categorized as less TEP. Results: 183 patients (men, 87.4%) who received ETR were less TEP and 413 patients (men, 91.0%) were more TEP. At baseline, more TEPs had more advanced disease, more previous antiretroviral (ARV) exposures and fewer options for active ARVs. At Week 96, for patients receiving ETR, response rates for the less TEP group and more TEP group were 68.3% and 52.8%, respectively. Incidence of adverse events (AEs) was similar between groups. A greater proportion of nonresponders in the more TEP group discontinued due to AEs (9.0% vs 5.5%) and virologic failure (18.9% vs 5.5%) compared with the less TEP group. Conclusion: Less TEPs had higher virologic response rates with ETR compared with more TEPs. Because the less TEP population from DUET more closely resembles TEPs with HIV-1 today, data from this subgroup may provide valuable information for real-life treatment decisions.

Small changes in the wording of health related recommendations about Sexually Transmitted Diseases (STDs) can significantly influence their impact. In this paper, we review advances in research investigating the content and structure of these framed messages. We also summarize the results of a recent longitudinal study examining the effects of a brief risk awareness intervention (i.e., a brochure) targeting young adults–the population at highest risk of contracting STDs. Building on a leading theory and emerging data, we review key aspects of the psychological processes that underlie the impact of framed messages on prevention and detection of STDs, and we detail how these messages can be made more influential when accompanied by visual aids. Our review converges with other research indicating that well constructed visual aids are often among the most highly effective, transparent, and ethically desirable means of health risk communication. Larger scale implementation of these and other theory-based, custom-tailored methods holds the promise of relatively inexpensive yet highly-effective systems for promoting prevention and detection of STDs.

Genotypic resistance test has been recommended to evaluate HIV drug resistance and guide the effective regimens of antiretroviral therapy (ART) in HIV-infected patients with treatment failure. In patients with multiple treatment failures, drug resistance-associated mutations may disappear due to the loss of selective drug pressure after switching regimens. A cohort study was conducted among HIV-infected patients who had ≥2 genotypic resistance tests during 2003-2011. HIV-1 pol nucleotide sequencing of reverse transcriptase and protease region was carried out using TRUGENE HIV-1 Genotypic Assay. Sequencing data was analyzed using Stanford rule-based interpretation algorithms. Of 54 patients with mean age of 30.1 years, 46.3% were males. HIV-1 subtype A/E was observed in 88.9% of patients. At the latest failure, 55.3% were receiving protease inhibitor-based regimens. Median CD4 and HIV RNA were 167 cells/mm³ and 22,359 copies/mL. During a median duration of ART of 38.6 months, 72.2%, 22.2%, and 5.6% had 5, 3, and 2 genotype tests, respectively. When compared between using cumulative (CG) and last genotypes (LG), CG interpreted resistance to any drug 59.3% higher than LG did. For NRTI, NNRTI, and PI drug classes, CG interpreted as resistance 42.6%, 27.8%, and 7.4% higher than LG, respectively. The most common drugs that CG interpreted resistance with the higher rate than LG were lamivudine/emtricitabine, nevirapine, efavirenz, etravirine and abacavir. In conclusion, CG interprets HIV drug resistance at a higher rate than LG and may be more accurate to use for selecting the next effective regimen of ART among HIV-infected patients with multiple treatment failures.