Interactions of HIV-1 Capsid with Host Factors and Their Implications for Developing Novel Therapeutics.

The Human Immunodeficiency Virus type 1 (HIV-1) virion contains a conical shell, termed capsid, encasing the viral RNA genome. After cellular entry of the virion, the capsid is released and ensures the protection and delivery of the HIV-1 genome to the host nucleus for integration. The capsid relies on many virus-host factor interactions which are regulated spatiotemporally throughout the course of infection. In this paper, we will review the current understanding of the highly dynamic HIV-1 capsid-host interplay during the early stages of viral replication, namely intracellular capsid trafficking after viral fusion, nuclear import, uncoating, and integration of the viral genome into host chromatin. Conventional anti-retroviral therapies primarily target HIV-1 enzymes. Insights of capsid structure have resulted in a first-in-class, long-acting capsid-targeting inhibitor, GS-6207 (Lenacapavir). This inhibitor binds at the interface between capsid protein subunits, a site known to bind host factors, interferes with capsid nuclear import, HIV particle assembly, and ordered assembly. Our review will highlight capsid structure, the host factors that interact with capsid, and high-throughput screening techniques, specifically genomic and proteomic approaches, that have been and can be used to identify host factors that interact with capsid. Better structural and mechanistic insights into the capsid-host factor interactions will significantly inform the understanding of HIV-1 pathogenesis and the development of capsid-centric antiretroviral therapeutics.

Retinaldehyde dehydrogenase 2 as a molecular adjuvant for enhancement of mucosal immunity during DNA vaccination.

In order for vaccines to induce efficacious immune responses against mucosally transmitted pathogens, such as HIV-1, activated lymphocytes must efficiently migrate to and enter targeted mucosal sites. We have previously shown that all-trans retinoic acid (ATRA) can be used as a vaccine adjuvant to enhance mucosal CD8+ T cell responses during vaccination and improve protection against mucosal viral challenge. However, the ATRA formulation is incompatible with most recombinant vaccines, and the teratogenic potential of ATRA at high doses limits its usage in many clinical settings. We hypothesized that increasing in vivo production of retinoic acid (RA) during vaccination with a DNA vector expressing retinaldehyde dehydrogenase 2 (RALDH2), the rate-limiting enzyme in RA biosynthesis, could similarly provide enhanced programming of mucosal homing to T cell responses while avoiding teratogenic effects. Administration of a RALDH2- expressing plasmid during immunization with a HIVgag DNA vaccine resulted in increased systemic and mucosal CD8+ T cell numbers with an increase in both effector and central memory T cells. Moreover, mice that received RALDH2 plasmid during DNA vaccination were more resistant to intravaginal challenge with a recombinant vaccinia virus expressing the same HIVgag antigen (VACVgag). Thus, RALDH2 can be used as an alternative adjuvant to ATRA during DNA vaccination leading to an increase in both systemic and mucosal T cell immunity and better protection from viral infection at mucosal sites.

HIV-1 matrix protein p17: a candidate antigen for therapeutic vaccines against AIDS.

The success in the development of anti-retroviral therapies (HAART) that contain human immunodeficiency virus type 1 (HIV-1) infection is challenged by the cost of this lifelong therapy and by its toxicity. Immune-based therapeutic strategies that boost the immune response against HIV-1 proteins or protein subunits have been recently proposed to control virus replication in order to provide protection from disease development, reduce virus transmission, and help limit the use of anti-retroviral treatments. HIV-1 matrix protein p17 is a structural protein that is critically involved in most stages of the life cycle of the retrovirus. Besides its well established role in the virus life cycle, increasing evidence suggests that p17 may also be active extracellularly in deregulating biological activities of many different immune cells that are directly or indirectly involved in AIDS pathogenesis. Thus, p17 might represent a promising target for developing a therapeutic vaccine as a contribution to combating AIDS. In this article we review the biological characteristics of HIV-1 matrix protein p17 and we describe why a synthetic peptide representative of the p17 functional epitope may work as a vaccine molecule capable of inducing anti-p17 neutralizing response against p17 derived from divergent HIV-1 strains.