Challenges in HIV Vaccine Research for Treatment and Prevention

Abstract

Many attempts have been made or are ongoing for HIV prevention and HIV cure. Many successes are in the list, particularly for HIV drugs, recently proposed also for prevention. However, no eradication of infection has been achieved so far with any drug. Further, a residual immune dysregulation associated to chronic immune activation and incomplete restoration of B and T cell subsets, together with HIV DNA persistence in reservoirs, are still unmet needs of the highly active antiretroviral therapy, causing novel "non-AIDS related" diseases that account for a higher risk of death even in virologically suppressed patients. These "ART unmet needs" represent a problem, which is expected to increase by ART roll out. Further, in countries such as South Africa, where six millions of individuals are infected, ART appears unable to contain the epidemics. Regretfully, all the attempts at developing a preventative vaccine have been largely disappointing. However, recent therapeutic immunization strategies have opened new avenues for HIV treatment, which might be exploitable also for preventative vaccine approaches. For example, immunization strategies aimed at targeting key viral products responsible of virus transmission, activation, and maintenance of virus reservoirs may intensify drug efficacy and lead to a functional cure providing new perspectives also for prevention and future virus eradication strategies. However, this approach imposes new challenges to the scientific community, vaccine developers, and regulatory bodies, such as the identification of novel immunological and virological biomarkers to assess efficacy end-points, taking advantage from the natural history of infection and exploiting lessons from former trials. This review will focus first on recent advancement of therapeutic strategies, then on the progresses made in preventative approaches, discussing concepts, and problems for the way ahead for the development of vaccines for HIV treatment and prevention.

Keywords: HAART; HIV-1 vaccine; clinical studies; functional cure; preclinical and clinical proof-of-concept studies; therapeutics.

Figures

Figure 1

Control of HIV-1 by vaccines that stimulate CTLs. Effect of various T cell-stimulating vaccines (key) on viral load over time (with infection on day 0) during natural infection with HIV or SIV, showing the decrease in viral load achieved without a vaccine (none), by CTL responses [partial control; as in Ref. (92), for example], by the RhCMV vaccine (slow eradication) (60, 61) and by a hypothetical vaccine that targets the virus at the site of infection (rapid eradication). Reproduced with permission from Ref. (61).

Figure 2

Vaccines that deal with HIV-1 variability. Construction of vaccines based on viral sequences in four viral isolates (top; simplified representation): horizontal lines indicate viral sequences; circles indicate sites of greatest variability between isolates (and potential escape mutations from CTL pressure; there may be more than two alternative sequences at each spot); and blue lines indicate regions of relative conservation (although in reality no region of HIV-1 is invariant). The mosaic vaccine (middle) is constructed to include the most common variants from the isolates in as few strands as possible while conserving naturally occurring sequence stretches. In the conserved region-containing vaccine (bottom), the relatively conserved regions (blue) are excised and then are “stitched” together (which creates an unnatural junctional region). The regions typically vary from 30 to 120 amino acids in length. Reproduced with permission from Ref. (63).

Figure 3

Outcome of DC infection in the absence or presence of Tat, anti-Env, and/or anti-Tat antibodies. Tat redirects HIV to RGD-binding integrins evading neutralization by anti-Env Abs and both anti-Env and anti-Tat Abs are required to block infection. Extracellular Tat released by infected neighbor cells binds to trimeric Env on HIV, decreasing recognition of C-type lectin receptors and promoting engagement of RGD-binding integrins, which are expressed by inflammatory DCs, macrophages, and endothelial cells (ECs) present at the site of infection. As a result, virions escape neutralization by anti-Env Abs directed against high mannose determinants and enters target cells upon binding to RGD-binding integrins. Anti-Tat Abs neutralize this binding, preventing virus entry through RGD-binding integrins. DC-SIGN: dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin; SIGN-R: homolog of DC-SIGN present on ECs; MR: mannose receptor [modified from Ref. (68)].