Current HIV Research - Volume 3, Issue 2, 2005

A central obstacle to the design of a global HIV vaccine is viral diversity. Antigenic differences in envelope proteins result in distinct HIV serotypes, operationally defined such that antibodies raised against envelope molecules from one serotype will not bind envelope molecules from a different serotype. The existence of serotypes has presented a similar challenge to vaccine development against other pathogens. In such cases, antigenic diversity has been addressed by vaccine design. For example, the poliovirus vaccine includes three serotypes of poliovirus, and Pneumovax(ρ) presents a cocktail of 23 pneumococcal variants to the immune system. It is likely that a successful vaccine for HIV must also comprise a cocktail of antigens. Here, data relevant to the development of cocktail vaccines, designed to harness diverse, envelope-specific Bcell and T-cell responses, are reviewed.

The transmission of HIV and the progression of HIV disease are influenced not only by a large number of human host factors, but also by certain correlates of the ever fluctuating virus quasispecies. The present review article aims at providing the current state of knowledge as well as an in-depth critical discussion of recent developments on the potential effects of HIV subtype, phenotype and attenuation on HIV disease. Despite the extensive research, several questions regarding the precise role that each of these correlates plays in human AIDS pathogenesis remain unanswered. Unraveling these roles is expected to aid the continued quest for truly effective antiretroviral drug regimens and preventive vaccines.

The inpatient presentation of the HIV infected patient has changed over the years. From the early years when patients presented with accumulating opportunistic infections that led to an early demise to the HAART era with reports of dramatic decreases in opportunistic infections and improvements in life expectancy, the evolution of inpatient HIV care has been a challenge to the clinician. In the HAART era the presentation of the HIV inpatient has diversified and in many ways is more challenging than the management of the HIV inpatient in the pre-HAART era. We will discuss the changing dynamics of HIV inpatient care from socioeconomic changes to changes in the presentation and reasons for hospitalization.

To promote the initiation of reverse transcription, the HIV-1 virus uses a host tRNA as a primer, L ys tRNA3 . The annealing of L ys tRNA3 to the viral RNA requires the breaking of the 3D structure of the tRNA and RNA rearrangements, to form a stable initiation complex recognised by the reverse transcriptase. The annealing is mediated by a viral factor, the nucleocapsid protein. This protein has been studied for a long while to define the role of its different sub-domains and their mode of action. Only recently, a consensus view seems to emerge. The structure of the initiation complex, is still discussed. The goal of this review is to clarify what is known about the formation and the structure of the tRNA/viral RNA complex and the role of the nucleocapsid protein from a structural point of view.

During the past 20 years, the development of HIV vaccines has come a long way. The focus has progressively changed from the traditional protein-based HIV vaccines that induce humoral immunity to the live recombinant viral vector-based HIV vaccines capable of eliciting both cellular and humoral immune responses. These new viral vector-based vaccines encoding multiple HIV antigens, delivered either alone or in heterologous prime-boost modalities elicited antigen-specific CTL responses in immunized hosts and protected animals from disease. The viral vector-based vaccines have proven to be potent vaccines in pre-clinical studies and foster the hope to put an end to the ever-increasing threat of the AIDS epidemic. Several unique features of viral vector-based HIV vaccines have contributed to their success, including their intrinsic immune-modulating properties, high transduction efficiency, and in vivo production of immunogens within the cell mimicking a natural infection without the associated health risks. In this review, we will discuss the characteristics of non-replicating viral vectors most commonly used for HIV vaccines with a particular focus on immune responses elicited by the vector particles alone and their effect on the potency of viral vector-based HIV vaccines.

We evaluated a low cost manual reverse transcriptase assay (ExaVir(ρ) Load V.1 and V.2; Cavidi Tech AB) against commercially available HIV RNA assays that quantify viral load to assess its suitability for use in resource-constrained settings. Frozen plasma samples previously tested for RNA by RT-PCR (Roche Diagnostics) and bDNA (Bayer Diagnostics) were retested for RT activity. Text sequence obtained from HIV genotype analysis was submitted to the Stanford HIV Resistance Database V.3.9 and were examined for resistant virus. Detectable RT was present in 98% of samples (V.1; n=127) and in 95% of samples (V.2; n=69) with RNA >10,000 and >1,000 copies / ml respectively. Positive association was found between the log10 RNA copies / ml and log10 RT copies / ml equivalents variables using Pearson's correlation (V.1: r=0.89, n=189; V.2: r=0.89, n=85). The RT activity over time closely followed the trend for RNA levels in samples from 10 HIV seropositive patients with progressive disease. A strong association between RT and RNA was also found with paired samples from 19 patients taken at initiation or change of antiretroviral therapy and again within 2 months. Current (n=40) or no (n=119) exposure to efavirenz therapy had no effect on RT assay performance despite efavirenz binding tightly to the RT enzyme. Samples that demonstrated resistance to the nonnucleoside RT inhibitors (n=112) had a decrease in RT of 0.20 log10 indicating a possible decrease in RT fitness. The RT assay showed good association with current molecular assays, and V.2 is sufficiently sensitive for monitoring HIV viral load in resource-constrained settings.

DNA vaccinations effectively induce both humoral and cellular immune responses to immunogens from diverse infectious agents. However, DNA vaccines expressing the HIV-1 envelope glycoprotein (Env) are poorly immunogenic when expressed from wild-type (wt) DNA sequences. Two recent approaches used to enhance the immunogenicity of Env expressed from a DNA vaccine are the fusion of the molecular adjuvant, C3d, to a soluble form of Env and the use of codon-optimized (co) env gene inserts. Independently, each approach enhances antibody titer and cellular responses against Env expressed from gene inserts. The goal of this study was to examine if both codon-optimization of env gene inserts and C3d conjugation to Env could function in a synergistic manner to enhance immunogenicity. Mice (BALB/c) were inoculated with decreasing doses (2.0 μg, 0.2 μg or 0.02 μg) of co DNA expressing Env alone or fused to three copies of murine C3d (mC3d3) gene. Mice vaccinated with the highest dose (2.0 μg) of DNA had high anti-Env specific antibody titers regardless of the addition of mC3d3. At lower doses (0.2 μg and 0.02 μg) of DNA, mice vaccinated with Env-mC3d3 had enhanced immune responses compared to mice vaccinated with DNA expressing Env only. In addition, mice vaccinated with Env-mC3d3 at the highest doses of DNA had enhanced interleukin-4 secreting cells, while mice vaccinated with the lowest dose of DNA had enhanced interferon-gamma secreting cells. Therefore, both codon-optimization of env sequences and C3d conjugation to Env appear to enhance anti-Env antibodies in an independent and additive manner.