Current HIV Research - Volume 11, Issue 6, 2013

The past few years have witnessed many promising advances in HIV prevention strategies involving preexposure prophylaxis approaches. Some may now wonder whether an HIV vaccine is still needed, and whether developing one is even possible. The partial efficacy reported in the RV144 trial and the encouraging results of the accompanying immune correlates analysis suggest that an effective HIV vaccine is achievable. These successes have provided a large impetus and guidance for conducting more HIV vaccine trials. A key lesson learned from RV144 is that assessment of HIV acquisition is now a feasible and valuable primary objective for HIV preventive vaccine trials. In this article we review how RV144 and other HIV vaccine efficacy trials have instructed the field and highlight some of the HIV vaccine concepts in clinical development. After a long and significant investment, HIV vaccine clinical research is paying off in the form of valuable lessons that, if applied effectively, will accelerate the path toward a safe and effective vaccine. Together with other HIV prevention approaches, preventive and therapeutic HIV vaccines will be invaluable tools in bringing the epidemic to an end.

Although immune correlates of protection for HIV vaccines have remained an intractable question, RV144 provided the first evidence that an HIV vaccine could provide protective efficacy against HIV acquisition. The study of correlates of risk has opened large and unforeseen avenues of exploration and hope for the most exciting time of HIV vaccine development. Several elements in the RV144 post-hoc analysis and recent macaque challenge studies suggest that antibodies directed against the V2 loop of gp120 are functional and may have played a protective role against virus acquisition. Several protective mechanisms against sexual transmission of HIV are evoked including blocking the gp120- α4β7 interaction and ADCC although possibly mitigated by high levels of Env-specific IgA, both mechanisms contributing at least partially to the protective effect. Several questions remain unanswered that will deserve intensive assessments, in particular, IgG and IgA Env antibodies in mucosal secretions, Env-specific IgG subclasses, cross-reaction of V2 antibodies, role of T-follicular helper cells, and B-cell memory. Whether RV144 correlates of risk are universal and apply at least partially to other populations at higher risk for HIV acquisition and other modes of transmission (rectal, injecting drug users) is unknown and remains to be explored. Future efficacy trials using the same vaccine concept tested in high-risk heterosexual populations and in men having sex with men may answer this question. In addition, the determination of early events in the pathogenesis among HIV-infected vaccine recipients based on current correlates knowledge would offer unprecedented information about correlates biomarkers in the peripheral blood and gut mucosa during early acute HIV infection.

Many efforts have been made in the worldwide quest for a prophylactic HIV vaccine to end the AIDS pandemic, but none has yet succeeded. The lessons learned have repeatedly informed us that the traditional or conventional approaches directly using the pathogens or subunits will not be sufficient for an effective HIV/AIDS vaccine. Recent advances in structure-based technology have shown some promise in the quest for a better immunogen in HIV vaccine development. According to the basic binding structural relationship of an antigen and an antibody, structurebased antigen design could bring some hope for the development of an effective vaccine against HIV.

The advent of pre-exposure prophylaxis (PrEP) and treatment as prevention (TasP) as means of HIV prevention raises issues of justice concerning how most fairly and equitably to apportion resources in support of the burgeoning variety of established HIV treatment and prevention measures and further HIV research, including HIV vaccine research. We apply contemporary approaches to social justice to assess the ethical justification for allocating resources in support of HIV vaccine research given competing priorities to support broad implementation of HIV treatment and prevention measures, including TasP and PrEP. We argue that there is prima facie reason to believe that a safe and effective preventive HIV vaccine would offer a distinct set of ethically significant benefits not provided by current HIV treatment or prevention methods. It is thereby possible to justify continued support for HIV vaccine research despite tension with priorities for treatment, prevention, and other research. We then consider a counter-argument to such a justification based on the uncertainty of successfully developing a safe and effective preventive HIV vaccine. Finally, we discuss how HIV vaccine research might now be ethically designed and conducted given the new preventive options of TasP and PrEP, focusing on the ethically appropriate standard of prevention for HIV vaccine trials.

A study was conducted in an HIV/AIDS Zimbabwean cohort to assess possible associations of pharmacogenetic variants with common adverse drug reactions (ADRs) during anti-retroviral treatment (ART) and/or tuberculosis (TB) treatment. Genotype and allele frequencies for CYP2B6 G516T, CYP2B6 T983C, CYP2A6*17, ABCB1 rs10276036 C>T, NAT2*5 and NAT2*14 were similar to those reported in literature for other African populations. The CYP2B6 516TT genotype and male gender were significantly associated with occurrence of Efavirenz induced central nervous system disorders (OR 20.58, p=0.004) and the ABCB1 rs10276036TT genotype with Nevirapine induced skin hypersensitivity (OR 4.01, p=0.04). For Stavudine, time on treatment was the main factor in development of lipodystrophy (OR 1.06, p<0.0001). For isoniazid, increasing patient age was associated with peripheral neuropathy (OR 1.05, p=0.001). Although genetic polymorphisms may play a role in predicting occurrence of ADRs, this study also indicates that other factors (gender, age, treatment time) are crucial in predicting drug-induced adverse effects.

Despite numerous and tremendous achievements in the development and standardization of HIV vaccines, there are still lots of vague concepts in HIV vaccinology. Various approaches have been applied to design an efficient HIV vaccine. Due to their lack of replication ability and expression of native antigens at the same time virus-like particles, such as previously introduced mzNL4-3 HIV-1 VLPs are among the highlighted candidates in this field. On the other part, application of adjuvants is an inseparable strategy in the vaccine development researches. Archaeosomes are liposomal adjuvants with intensifiying features of T helper 1 and cytotoxic T-cells responses. Archaeosomes derived from Methanobrevibacter smithii has been shown to enhance MHC class I-dependent antigen presentation and hence, are to be advantageous in the development of vaccines against viral infections. Herein, we have studied efficiency of mzNL4-3 VLPs entrapped in M. smithii archaeosomes as an HIV-1 vaccine candidate to induce humoral and cellular responses in BALB/c mice. Analysis of total and subtype-specific anti-Env IgG antibody, as well as, cytokine secretion pattern revealed an efficient promotion of anti-HIV specific T helper 1 responses in immunized animals. This finding was evidenced by the significant dominance of IgG2a subtype in the sera and considerable secretion of IFN-γ by specifically induced splenocytes of mice immunized with VLP-containing archaeosomes (VLP+ Archaeosome). In addition, ELISpot assay verified these results and indicated the significantly higher frequency of IFN-γ secreting splenocytes in immunized models. The ratio of IFN-γ to IL-4 spot forming cells (SFCs) in the VLP+ Archaeosome immunized mice was also higher than that of the other groups immunized with either VLP-free archaeosomes or VLPs formulated with complete/incomplete Freund’s adjuvants. These results propound M. smithii archaeosomes-entrapped mzNL4-3 VLPs as a promising immunogen which specifically induces and augments T-helper 1 oriented responses against HIV antigens.

The prevalence of orofacial and systemic manifestations and their association with drug therapy in pediatric HIV patients is scarce in the literature. The aim of the study was to determine the prevalence of oro-facial and systemic manifestations in HIV sero-positive children with and without highly active antiretroviral therapy (HAART). The study population consisted of 100 pediatric HIV patients (n=47 on HAART and n=53 not on HAART). The majority of the children (n=56) had at least one or more oro-facial manifestation associated with HIV. Oral candidiasis was the most common oral finding present in the HAART (14/33) and non-HAART groups (19/33). Recurrent aphthous ulcers was the only significant oral finding, present more in the HAART group. The percentage of children with upper respiratory tract infection was also more in the HAART group. The other lesions which were found to be significant were seborrheic dermatitis, pulmonary tuberculosis and otitis media. There was no significant difference in the participants’ oral findings based on CD4 counts in the HAART and non- HAART groups. The prevalence of oral and systemic manifestations is a persistent feature associated with pediatric HIV, though of moderate intensity in those using HAART and may vary according to individual immune status.

C-C chemokine receptor type 5 (CCR5) is known for its role as a co-receptor for HIV-1 infection. Some individuals possess a 32 bp deletion, known as Delta-32 allele which has been reported to confer resistance to HIV-1 infection. In order to estimate the distribution of Delta-32 allele of CCR5 gene, 1034 mestizo individuals from the Northwest of Mexico, including 385 HIV-1-infected individuals, 472 healthy controls and 177 uninfected female sex workers; were examined by allele-specific PCR. There was no statistically significant difference in the frequency of Delta-32 allele between HIV-1 positive and healthy individuals (OR= 1.1, p= 0.6). However, we found a significantly reduced prevalence of CCR5 Delta-32 heterozygous genotype in female patients (OR= 0.084, 95% CI= 0.011 - 0.630, p= 0.002), as well as in allele frequency, compared to male patients. Furthermore, we observed an inverse relationship between allele frequency and the risk of HIV-1 transmission and AIDS progression among female healthy controls, sex workers and HIV-1 infected groups. Our findings support previous data showing Delta-32 as a genetic protective factor against HIV-1 infection in Mexican women, as well as in women from other populations.