Current HIV Research - Volume 8, Issue 6, 2010

The persistence of latent HIV-infected cellular reservoirs represents the major hurdle to virus eradication on patients treated with HAART. It has been suggested that successful depletion of such latent reservoirs will require a combination of therapeutic agents that can specifically and efficiently act on cells harboring latent HIV-1 provirus. Using Jurkat-LAT-GFP cells, a tractable model of HIV-1 latency, we have found that bryostatin-1 reactivates HIV-1 through a classical PKC-dependent pathway. Bryostatin-1 also activates MAPKs and NF-κB pathways and synergizes with HDAC inhibitors to reactivate HIV-1 from latency. Bryostatin-1 downregulates the expression of the HIV-1 co-receptors CD4 and CXCR4 and prevented de novo HIV-1 infection in susceptible cells. We applied proteomic methods to investigate major changes in protein expression in Jurkat-LAT-GFP under latency and reactivation conditions. We identified upregulation of proteins that may be involved in the innate anti-HIV-1 response (NKEF-A and MHD2) and in different cell functions (i.e. cofilin-1 and transgelin-2) of the host cells. PKC agonists may represent a valuable pharmacological approach to purge latent HIV from cellular reservoirs and at the moment, the only clinically available PKC agonist is bryostatin-1. This drug has been tested in numerous clinical trials and its pharmacokinetics and toxicity in humans is well known. Moreover, bryostatin-1 potently synergizes with other HDAC inhibitors commonly used in the medical practice such as valproic acid. Therefore, bryostatin-1, alone or in combination with HDAC inhibitors, could be used in HAART treated patients to validate the hypothesis that reactivating HIV-1 from latency could purge HIV-1 reservoirs.

Most new HIV infections in sub-Saharan Africa now occur in married and cohabiting couples, many of whom do not realize that only one of them may be infected with HIV. HIV-negative individuals living in stable HIV-discordant partnerships (in which one partner is HIV-infected while the other one is not) are twice as likely to get infected with HIV as those living in concordant HIV-negative relationships. Since HIV transmission occurs mainly from HIV-infected persons who are unaware of their status, a combination of interventions including behavioral and biomedical interventions is urgently needed to increase knowledge of HIV status as well as reduce the risk of HIV transmission within married and cohabiting couples. Behavioral interventions include promotion of couples' counseling, testing and disclosure; condom promotion as well as alcohol risk-reduction, while biomedical interventions include provision of antiretroviral treatment to the HIV-infected partner, medical male circumcision and treatment of sexually transmitted infections. Since no single intervention can turn around the current HIV tide in married and cohabiting couples, we argue for the inclusion of these interventions in a combination prevention package for married and cohabiting HIV-discordant couples in sub-Saharan Africa.

The development of a safe and effective HIV vaccine remains the best hope to control the global HIV epidemic. So far, the different strategies tried for vaccine development have led to disappointing results. The first attempted strategy involved trying to raise neutralizing antibodies to inactivate the virus and prevent infection. Both of Vaxgen's VAX004 and VAX003 phase 3 trials made use of this approach but ultimately failed. Given the difficulties encountered, the focus then shifted to the cell mediated arm of the immune system, the T lymphocytes. However, the phase 2 STEP study, which was aimed to stimulate cell-mediated immunity, was halted in 2007 because it failed to prevent infection and there was an increased incidence of HIV infection in vaccinated individuals. Many researchers now believe that vaccine candidates need to induce both sustained broadly neutralizing antibodies and a strong cell-mediated response. Therefore, attention is now focused on the prime-boost approach: a DNA or vector vaccine to elicit cytotoxic T cells that destroy infected cells followed by a subunit vaccine to induce neutralizing antibodies. RV144, the largest ever HIV vaccine trial, used a prime-boost combination vaccine, which was shown to be safe and modestly effective. The ongoing RV152 study will provide more information on the modest degree of efficacy of the RV144 vaccine with results expected in 2013. Finally, the ongoing HVTN 505 trial also makes use of the prime-boost strategy and is expected to provide a better understanding of T-cell-based vaccines. In this review, we discuss the results of all the above-mentioned trials and consider whether an HIV vaccine needs to induce both humoral and cellular immunity to be effective.

Skin and mucosal diseases can be the first manifestation of asymptomatic HIV infection, may indicate advancing immunodeficiency, or may represent systemic opportunistic infections or neoplasms. Mucocutaneous diseases are highly prevalent in the HIV-infected population and multiple pathologies are common particularly with advanced immunosuppression. The dominant HIV-associated skin diseases are infectious and inflammatory and they can cause significant morbidity. Although skin cancers are less common their prognosis is often worse. Clinical presentations are often atypical and may vary depending on the level of immunosuppression. Managing skin disease in the context of advanced immunosuppression is challenging and they often respond poorly to conventional therapies. This improves with the commencement of antiretrovirals (ARVs) and immune restoration. Despite the significant decline in HIV-related skin diseases with ARVs, the drugs themselves have brought with them a range of other skin-associated problems: adverse effects, an increased risk of drug reactions, and immune reconstitution-associated skin diseases. Therefore, the burden of skin disease remains high even in the era ARVs and the aim of this review is to equip physicians managing HIV-infected patients with knowledge of the spectrum of skin disorders associated with HIV-related immunosuppression.

Protease inhibitor (PI) resistance-associated mutations (RAMs) are commonly observed in PI-naive patients who are infected with HIV-1 subtype A/E. Few data are available on the genetic mechanisms of PI resistance in non-B HIV-1. This study was aimed to compare PI-RAMs between PI-naive and -experienced patients and determine PI resistance in each group. Genotypic resistance testing was conducted among a cohort of HIV-1-infected patients who were diagnosed with virologic failure. We studied 137 patients of whom 75 patients were in PI-naive group and 62 patients in PI-experienced group. Median CD4 cell count and HIV-1 RNA at virologic failure were 169 cells/mm3 and 14,100 copies/mL, respectively. The clinical characteristics between 2 groups were similar (p>0.05) except for the duration of antiretroviral therapy (ART) which was shorter in PI-naive group (31.5 vs 46.8 months, p=0.028). Proportion of patients with primary PI-RAMs was 2.7% in PI-naive and 19% in PI-experienced groups (p=0.002). The most common primary PI-RAMs in the latter group were V82A (10%), I54V (7%) and G48V (4.8%). Proportion of patients with secondary PIRAMs in the corresponding groups was 99% and 98%, respectively (p=1.000). The most common secondary PI-RAMs in both groups were M36I (91%), H69K (34%) and L89M (30%). In conclusion, primary PI-RAMs are observed exclusively among PI-experienced patients, whereas secondary PI-RAMs are equally found in both PI-naive and PI-experienced patients. Further studies to define virologic response of HIV-1 subtype A/E to various PIs and clinical validation of PIRAMs in HIV-1 subtype A/E are essentially needed.

Background: Vaccination of asymptomatic human immunodeficiency virus (HIV)-infected patients with a CD4 cell count ® 200/mm3 is strongly suggested prior to travel to a region where yellow fever (YF) is endemic. However, few data describing YF vaccination in such patients are available. Methods: In this retrospective observational study of 23 HIV-infected patients, YF antibody titers, CD4 cell counts, and viral loads were measured before and after vaccination. Serologies were performed retrospectively on samples that had been stored as part of routine hospital procedures. Results: Ninety-three percent of patients (13/14) with no baseline immunity, seroconverted after vaccination. Immunogenicity appeared slowly; only 2 of the 5 patients tested within 5 weeks of vaccination had seroconverted. A booster effect was noted in 3 of the 9 patients with baseline immunogenicity. Finally, due to unawareness of his HIV status, one patient was vaccinated and was found later to have a CD4 cell count < 200/mm3. The YF vaccine was well tolerated and no serious adverse events were reported. The impact of vaccination on immunologic and viral parameters was variable. Both decreases (n = 7) and increases (n = 5) in CD4 cell counts were recorded. Viral loads became undetectable in 2 patients and doubled or became positive in 3 patients. Conclusions: Yellow fever vaccination was safe and effective in a large majority of this cohort of stable, HIV-infected patients.

Background: The high antiviral potency and low toxicity of saquinavir/ritonavir (SQV/r) prompted us to assess a viable strategy in chronic virologically suppressed HIV-infected patients. Methods: A randomized, multicenter pilot trial. Patients taking triple HAART with (VL <50 copies/mL) and no history of virological failure with a protease inhibitor (PI) or PI-related resistance were assigned in a 2:1 ratio to receive SQV 1000 mg/ritonavir 100 mg BID (SQV/r group) or to continue with their habitual treatment (control group). Comparisons were performed using the Mann-Whitney test for medians, the t test or ANOVA for means, and the χ2 or Fisher's exact test for proportions. Results: 28 patients were randomized: 17 to the SQV/r group and 11 to the control group. Only 1 patient from the SQV/r group experienced virological failure at week 48. A similar mean increase was observed in CD4+ T-cell counts in both groups at week 48. Three patients (17.6%) from the SQV/r group prematurely interrupted the study for reasons other than virological failure. HDL cholesterol increased significantly at week 48 in the SQV/r group (from 41±11 mg/dL to 56±35, P=.026); patients in the control group showed a decrease in LDL cholesterol (from 129±37 mg/dL to 107±17, P=.028). The median (IQR) trough plasma concentrations of SQV were 760 ng/mL (379.5-1332.25 ng/mL). Three patients had saquinavir concentrations lower than 100 ng/mL. Conclusion: SQV/r as monotherapy has proven to be a valid, safe, and economical option for virologically suppressed HIV-infected patients, especially in those who experience intolerance or toxicity with nucleoside analogs.

The study of clinical and demographic characteristics related to virus control and disease progression in patients who spontaneously control HIV vireamia (HIV-controllers) is of major interest. A particular cause of HIV control has not been found and the scenario could be partially explained by special homeostatic and immunological features. In this study, CD57+CD28- phenotype, T-cell activation and levels of proliferating T-cells in elite-controllers were studied in relation to spontaneous virus control. In HIV-controllers, 9% were AIDS-diagnosed and there was a high proportion of women. In elite-controllers, high T-cell CD57+CD28- phenotype and activation levels were found and, interestingly, there was a low proliferation of total and naive T-cells and a high proliferation of the CD4+ TEMRA subset. Low T-cell proliferation and preferential expansion of terminally differentiated effector T-cell subsets could be an important factor for virus control in elite-controllers.

Objectives: to analyze the long-term immunovirological effect and tolerability of a maraviroc-containing antiretroviral therapy in viraemic and pretreated HIV-infected patients with a high prevalence of hepatitis C virus (HCV) coinfection. Methods: forty-six R5 HIV-infected patients (48% HCV-coinfected) started a maraviroc-containing antiretroviral regimen, including patients with multidrug resistant virus and patients after first virologic failure. A retrospective study was performed, analysing percentage of patients with undetectable viral load, mean CD4+ gain, liver enzymes, clinical events and treatment modification up to week 48. Results: Raltegravir plus a boosted protease inhibitor was combined with maraviroc in 65.2% of the patients (mainly patients with multidrug resistant virus), while the coformulation lamivudine/abacavir was combined with maraviroc in 26.1% (all of them patients after first virologic failure). After 48 weeks on maraviroc-containing regimen, 96.3% of the patients had achieved undetectability and a mean CD4+ count increase of 151 cells/mm3 was observed. Liver enzymes did not increase along the follow up. One patient died after 24 weeks follow up due to heroin overdose. One patient developed a non-Hodgkin lymphoma after 36 weeks follow up, despite undetectable viral load and significant CD4+ increase was achieved (the only AIDS-defining event observed). Treatment modification was performed in 19.6% of the patients: 77.7% of them experienced a treatment simplification and only 1/46 suspended maraviroc. Conclusions: maraviroc-containing regimen is long-term effective and well tolerated in HIV-infected patients in routine clinical practice and in different clinical scenarios.

Vitamin-D-receptor (VDR) mediates immunomodulatory effects of vitamin-VD3 (VD3). The VDRrs1544410_ GG polymorphism has been associated with delayed progression rates to AIDS and resistance to HIV-1 infection. The aim of the present study was to investigate differences in VD3 mediated effects on rs1544410 genotyped dendritic cells (DCs) and macrophages (MDM), key cells involved in HIV-1 infection. Immature DCs exhibited lower bactin- normalized VDR mRNA expression in rs1544410_GG compared to cells with a rs1544410_AA genotype. VD3 response on cell differentiation markers (CD14 inhibition and CD209 induction) was two-fold higher in rs1544410_AA (CD209, p=0.012; CD14, p=0.02). HIV-1-LTR reporter gene activity in MDM was boosted by VD3 ; however, the effect was up to 50% higher in rs1544410_AA. We conclude that the rs1544410_AA association with progression to AIDS and resistance to HIV-1 appears to be linked to an enhanced response to VD3.