Current HIV Research (v.10, #2)

The 30 years of the human immunodeficiency virus (HIV) epidemic have been marked by many triumphs. Today, thanks to life-saving anti-retroviral medications, patients are living longer than ever. However, despite scientific advances in the field of HIV treatment, HIV prevention has had less success. Despite efforts on several fronts, the number of new HIV diagnoses each year in the United States is unchanged. In this review, we will give a brief overview of the ups and downs of the field of HIV prevention, focusing on pre-exposure prophylaxis (PrEP). CAPRISA 004, iPrEx, FEMPREP, the VOICE trial and HPTN 052, among other prevention trials, are discussed. The CAPRISA 004 and iPrEx studies suggest optimism regarding the use of PrEP for those at risk for HIV infection, but the recent early termination of FEM-PREP and of one arm of VOICE has led to tempered enthusiasm. Many questions remain: Who should get PrEP? How long is it safe to take PrEP? What role will adherence play, and will there be problems with acquired resistance to the drugs with larger numbers using it daily? What is the best method of administering PrEP? Pre-exposure prophylaxis alone is unlikely to be the magic bullet- instead, this strategy will likely need to be part of a broader test-and-treat effort, ongoing education, treatment of sexually transmitted infections, and condom use.

Implementation of highly active antiretroviral therapy (HAART) has deeply changed the landscape of HIVassociated malignancies. Some AIDS-defining tumors, namely Primitive Lymphoma of Central Nervous System, have drastically declined, whereas a steady increase has been observed for non-AIDS-defining tumors, maybe due to longer survival of HIV-infected people. Easier immune restoration, subsequent to availability of a number of drugs targeting HIV at different points, has decreased opportunistic infections which hampered treatment of HIV-associated cancers. As a matter of fact these patients have been assimilated more and more with their negative counterpart, undergoing the same aggressive approach. Consistently, procedures that have been so far precluded to HIV+ subjects, such as transplant of hemopoietic stem cells, either autologous or allogenic, and liver transplant are expected to be performed more and more extensively in this population. Which also would mean a full removal of the stigma which has weighed on it. Hence, it is true-like that malignancies and related problems may in the next future make up a main concern for the HIV specialist. Old and new challenges might be the drug-drug interaction of antiretrovirals or biotherapy-related infections or the debated question of an earlier HAART implementation in the course of HIV disease, with CD4+ cells > 500/μl. In fact, if assimilation of HIV patients with cancer and the general population is a remarkable achieved goal, uniqueness of HIV infection in terms of immune status still makes HIV-associated cancer a unique chapter in the setting of Oncology.

Viral diversity plays an important role in the pathogenesis of HIV disease. However, within an individual, HIV can vary substantially from one tissue or cell type to another, thereby creating viral compartments. HIV compartmentalization has been well documented in the brain, cerebrospinal fluid, and genital tract, although there are also data for viral compartmentalization within the gut, lung, liver, kidney, and breast milk. The precise mechanisms that lead to the development of HIV compartmentalization have not been adequately examined but likely include differential immune selection pressures, cell type-specific differences in replication or gene expression, local concentrations of antiviral drugs and/or drug resistance, and co-infections that alter the cellular microenvironment. Identifying and characterizing distinct viral sub-populations enhances our overall understanding of HIV pathogenesis and could ultimately result in the development of novel strategies to impair the ability of these viruses to adapt to and/or infect a given cell/tissue type.

Interleukin 7 (IL7) is a critical factor for lymphocyte homeostasis. A dysfunction of the IL7/IL7R pathway has previously been described in HIV-1 infection, and promising results were observed in recent analyses of IL7 for therapeutic use in HIV infected individuals. However, further investigations are still warranted to understand the possible roles of this cytokine. Here, we explored whether the IL7 and IL7RA genetic polymorphisms were associated with the progression of HIV infection. We extensively genotyped the IL7 and IL7RA genes in the GRIV (Genomics of Resistance to Immunodeficiency Virus) cohort, composed of patients with extreme progression profiles - long-term non (LTNP) and rapid (RP) progressors -, and in a healthy control group (CTR). Statistical case-control analyses were performed using the Fisher's exact test, comparing either LTNP vs CTR or RP vs CTR. Three IL7RA SNPs (single nucleotide polymorphisms - rs7701176, rs987106 and rs10491434), but no IL7 SNPs, were significantly associated with rapid disease progression (Pμ0.01). In a multi-marker analysis focusing on functional variants, a strong association between an IL7RA haplotype and rapid progression was observed (P=5.59x10-3). In summary, our comprehensive genetic study revealed three SNPs and a risk of haplotype associated with rapid progression to AIDS in the IL7RA gene. Interestingly, the haplotype is composed of SNPs previously identified in other inflammatory diseases (e.g., multiple sclerosis) by GWAS and by functional studies. Our results contribute to the growing understanding of the role of IL7/IL7R in HIV disease progression, and more widely, in CD4+ T cell homeostasis.

CRF_BC recombinant strains were first identified in China and are one of the most prevalent and characteristically unique HIV-1 subtypes across China. Here we aim to review the published data about HIV-1 CRF_BC recombinant strains epidemic in China and to characterize the genetics, biology and drug resistance of this virus. This study may help to better understand the current situation of HIV-1 CRF_BC prevalence and facilitate the development of vaccines and more efficient anti-HIV-1 regimens in China.

Sildenafil is increasingly used for the therapy of pulmonary arterial hypertension (PAH) in HIV infected patients. However, concerns exist about pharmacokinetic interactions between sildenafil and protease inhibitors (PI); in particular, ritonavir has been shown to increase sildenafil AUC and Cmax by several folds. The aim of our study was to determine the plasma levels of sildenafil and PI in two HIV patients with PAH treated with antiretroviral therapy including ritonavir-boosted PI. Our patients both experienced sildenafil Cmax above 500 ng/mL; however, they did not report any significant adverse reactions to sildenafil during the follow-up period. Therapeutic drug monitoring of sildenafil should be taken in consideration during treatment in order to avoid overdosage.

Human immunodeficiency virus (HIV) infected individuals are prone to malnutrition, and deficiencies of some minerals and vitamins. The aim of this study is to evaluate the frequency of vitamin D deficiency and determine the possible risk factors associated with this problem in HIV-infected individuals. This cross-sectional study was performed on 98 adult patients referred to the Emam Khomeini Hospital Complex, Tehran, Iran. The patients' serum vitamin D concentration was determined using radioimmunoassay method. The possible correlations between demographic and clinical data with the level of vitamin D were evaluated. Vitamin D levels less than 35 nmol/l were considered as deficient in this study. Eighty-five (86.7&#x25;) of the patients had serum vitamin D deficiency (concentrations less than 35 nmol/l) in this study. Coinfection with hepatitis C virus (HCV) was present in 54 (55.1&#x25;) of the patients. Only daily intake of vitamin D (r=0.304, p=0.002), duration of sun exposure (r=0.268, p=0.009), the level of PTH (r=-0.459, p < 0.001), daily intake of calcium (r=0.239, ps0.018) and GFR of more than 90 ml/min (OR=1.208, CI 95&#x25;= 1.080-1.350, p=0.033) had a correlation with serum vitamin D concentration. Being female (OR=7.224, CI 95&#x25;= 3.640-14.335, p < 0.001), unemployed (OR= 1.627, CI 95&#x25;=1.209-2.190, p < 0.001) and infected with HCV (OR= 1.811, CI 95&#x25;= 1.331-2.465, p < 0.001) were related to the severe serum vitamin D deficiency. Vitamin D deficiency is a common problem in Iranian HIV-infected patients and with concern of this vitamin's important role in health issues, early evaluation of its status and providing appropriate nutritional support seems to be important.

Long-term potent activity of antiretrovirals is essential for HIV-1-infected, treatment-experienced patients. TITAN (TMC114/r In Treatment-experienced pAtients Naive to lopinavir) compared Week-96 efficacy and safety of darunavir/ritonavir (DRV/r) versus lopinavir/ritonavir (LPV/r). Treatment-experienced, LPV-naive, HIV-1-infected patients were randomised to DRV/r 600/100 mg bid or LPV/r 400/100 mg bid plus optimised background regimen (&#x2265; 2 NRTIs/NNRTIs). 595 patients were enrolled (mean baseline HIV-1 RNA: 4.30 log10 copies/mL; median CD4 count: 232 cells/mm3). At Week 96, more DRV/r than LPV/r patients achieved HIV-1 RNA < 400 copies/mL (66.8&#x25; versus 58.9&#x25; [intent-to-treat (ITT)/time-to-loss of virological response (TLOVR)], estimated difference 8.7&#x25;, 95&#x25; confidence interval [CI]: 0.7-16.7), demonstrating the primary endpoint of non-inferiority of DRV/r (p < 0.001); the difference in response was statistically significant (p=0.034). For the secondary efficacy parameter (HIV-1 RNA < 50 copies/mL) at Week 96, response to DRV/r was 60.4&#x25; versus 55.2&#x25; for LPV/r (ITT-TLOVR), estimated difference 5.8&#x25;, 95&#x25; CI: -2.3-13.9. Virological failure (VF; HIV-1 RNA > 400 copies/mL) with DRV/r (13.8&#x25;) was nearly half that with LPV/r (25.6&#x25;). Discontinuations due to adverse events were 8.1&#x25; for both DRV/r and LPV/r. Treatment-related grade 2-4 diarrhoea was 8.1&#x25; (DRV/r) versus 15.2&#x25; (LPV/r). Increases in triglycerides and total cholesterol were less pronounced with DRV/r. At 96 weeks, noninferiority (HIV-1 RNA < 400 copies/mL) of DRV/r over LPV/r was maintained; the difference in response was statistically significant. VF rate and treatment-related grade 2-4 diarrhoea were lower with DRV/r versus LPV/r.

Enfuvirtide (T20), the first FDA approved fusion inhibitor for HIV-1/AIDS, displayed outstanding effects of fusion inhibition by binding to the envelope glycoprotein gp41. But with the continuous emergence of T20-resistant mutations, the exploration of T20's binding mechanism onto gp41 wild type (WT) and the related resistance mechanism is needed. In this work, a complete structure model of gp41 including the fusion peptide (FP) and HR1 in complex with three molecules of T20 was obtained by structural modeling and molecular dynamics simulation (MDS). In this T20-gp41 model, the T20 hydrophobic C-terminal composed of the eight-residue sequence &#x201C;WASLWNWF&#x201D; formed unstructured coil instead of a helical structure, which enabled more residues of T20 to contact gp41 to exert its antiviral activity. Essential residues Trp155, Trp159, Trp161 and Phe162 of T20 formed strong vdW interactions with some hydrophobic cavities on the gp41, as never seen in other gp41 trimetric core structures. Based on the T20-gp41 model, seven corresponding structure models of T20-resistant mutants G36D, I37K, V38E, Q39H, Q41R, N43D and L45M were constructed and fully equilibrated by MDS. Most remarkably, the I37K and Q41R mutations led to collapse of the coiled coil structure, causing greatest change in binding energy. Also notably, the V38E and N43D mutations hindered the binding of T20 through electrostatic repulsion and thus also resulted in dramatic change in binding energy. Besides, mutations G36D, Q39H and L45M only caused minor conformational and energetic changes. In all, these results could provide new clues for the design of T20-like peptide inhibitors to target the T20-resistant virus.