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.

Multifarious immunotherapeutic approaches to cure HIV-1 infection

“…That said, even administered in the context of cART, therapeutic immunization is likely to have little efficacy if used without other concomitant immunotherapies due to the immunocompromised status of chronically HIV-1-infected patients. 20 In a study we recently conducted, we hypothesized that HIV-1-specific responses would be enhanced by the administration of cytokines and recombinant human growth hormone (rhGH) in chronic treated HIV-1 infection. 17 Timing and delivery route of immunization were carefully considered in order to achieve the most robust antigen-specific responses.…”

“…20,24 Given the renewed interest in therapeutic vaccines as a component of latency reversal strategies, it is of utmost importance to determine the optimal timing and route of administration, in addition to the choice of immunogen.…”

“…However, immunization in conjunction with cART may lead to a reversal of anergy by selective induction and activation of specific memory T-cell responses against a number of viral proteins. 3,20 By presenting viral proteins in novel ways, with or without specific adjuvants, or by presenting both immunodominant and subdominant epitopes, specific beneficial memory responses may be induced or augmented, 13 and T-cell anergy reversed. That said, even administered in the context of cART, therapeutic immunization is likely to have little efficacy if used without other concomitant immunotherapies due to the immunocompromised status of chronically HIV-1-infected patients.…”

Recent advance in the structural analysis of HIV-1 envelope protein

“…Significant advance in chemotherapy has made HIV-1 infection as a chronic manageable disease in developed countries. Another arm of intervention, a vaccine against HIV-1, is unfortunately not with us yet [1,2]. However, our understanding of the structure of the envelope protein (Env) of HIV-1, a major target of vaccine, is significantly advanced in recent years.…”

HIV: Problems and Perspectives

“…The reason to start the treatment having the number of 350-500 cells / µl CD4-lymphocytes or more appears neurocognitive disorders, kidney disease, the presence of a tumor, chronic viral hepatitis B and C, autoimmune, and cardiovascular diseases [7]. Drug treatment should consider the peculiarities of the use of different classes of antiviral drugs: nonnucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs), fusion inhibitors, CCR5 antagonists (CCR5s) (inhibitors of entry), integrase strand transfer inhibitors (INSTIs) [8]. It was found that the treatment with one or two drugs has short therapy effect due to the rapid emergence of mutant forms of the virus with reduced susceptibility to antiretroviral drugs.…”