Current HIV Research - Volume 18, Issue 2, 2020

The HIV epidemic in Thailand in the 1980’s compromised the country’s socio-economic development. The epidemic first became evident in the community of men with male sexual partners (MSM), and subsequently spread to intravenous drug users (IVDU), female commercial sex workers (CSW) and their male clients, and, ultimately, to their partners and children. The HIV epidemic has devastated the country’s working-age population. The extensive negative impact and social stigma associated with the disease do not only have an impact on the victims of HIV but also on their descendants and relatives. An epicenter of the HIV epidemic has been in the northern provinces of Thailand. An HIV-1 subtype CRF01_AE, a complex chimeric virus composed of both A and E subtypes, is prevalent in Northern Thailand. The virus has quickly become a predominant viral strain circulating in Thailand, other neighboring Southeast Asian countries, and China as well as some other countries throughout the world. The epidemiology, evolution, and biology of CRF01_AE offer a unique model for further scientific investigations which would advance the knowledge of and curative strategies against HIV. In addition, Thailand has developed suitable national guidelines on HIV/AIDS treatment and prevention in order to control the epidemic. Effective antiretroviral drugs are, therefore, able to be made available to those who live with HIV. The national surveillance system has also been effective. The great efforts and resources which Thailand has dedicated to the fight against the epidemic have eventually paid off. In 2010, a plan was proposed to eliminate mother-to-child HIV transmission and Thailand has become the first country to be effective in this objective. Thailand therefore has become recognized as being the global leader in HIV prevention and treatment. The experience which Thailand has gained from the past and the current research and management strategies of the HIV epidemic has prepared the country for emerging strains of HIV-1 in the future.

Background: To complete its replication cycle, HIV-1 requires the nucleocytoplasmic export of intron-containing viral mRNAs. This process is ordinarily restricted by the cell, but HIV overcomes the block by means of a viral protein, Rev, and an RNA secondary structure found in all unspliced and incompletely spliced viral mRNAs called the Rev Response Element (RRE). In vivo activity of the Rev-RRE axis requires Rev binding to the RRE, oligomerization of Rev to form a competent ribonucleoprotein complex, and recruitment of cellular factors including Crm1 and RanGTP in order to export the targeted transcript. Sequence variability is observed among primary isolates in both Rev and the RRE, and the activity of both can be modulated through relatively small sequence changes. Primary isolates show differences in Rev-RRE activity and a few studies have found a correlation between lower Rev-RRE activity and slower progression of clinical disease. Lower Rev-RRE activity has also been associated with the evasion of cytotoxic T lymphocyte mediated killing. Conclusion: The HIV-1 Rev-RRE regulatory axis is an understudied mechanism by which viral adaptation to diverse immune milieus may take place. There is evidence that this adaptation plays a role in HIV pathogenesis, particularly in immune evasion and latency, but further studies with larger sample sizes are warranted.

Modern combination antiretroviral therapy (cART) can bring HIV-1 in blood plasma to level undetectable by standard tests, prevent the onset of acquired immune deficiency syndrome (AIDS), and allow a near-normal life expectancy for HIV-infected individuals. Unfortunately, cART is not curative, as within a few weeks of treatment cessation, HIV viremia in most patients rebounds to pre-cART levels. The primary source of this rebound, and the principal barrier to a cure, is the highly stable reservoir of latent yet replication-competent HIV-1 proviruses integrated into the genomic DNA of resting memory CD4+ T cells. In this review, prevailing models for how the latent reservoir is established and maintained, residual viremia and viremic rebound upon withdrawal of cART, and the types and characteristics of cells harboring latent HIV-1 will be discussed. Selected technologies currently being used to advance our understanding of HIV latency will also be presented, as will a perspective on which areas of advancement are most essential for producing the next generation of HIV-1 therapeutics.

The vast genetic variability of HIV has impeded efforts towards a cure for HIV. Lifelong administration of combined antiretroviral therapy (cART) is highly effective against HIV and has markedly increased the life expectancy of HIV infected individuals. However, the long-term usage of cART is associated with co-morbidities and the emergence of multidrug-resistant escape mutants necessitating the development of alternative approaches to combat HIV/AIDS. In the past decade, the development of single-cell antibody cloning methods has facilitated the characterization of a diverse array of highly potent neutralizing antibodies against a broad range of HIV strains. Although the passive transfer of these broadly neutralizing antibodies (bnAbs) in both animal models and humans has been shown to elicit significant antiviral effects, long term virologic suppression requires repeated administration of these antibodies. Adeno-associated virus (AAV) mediated antibody gene transfer provides a long-term expression of these antibodies from a single administration of the recombinant vector. Therefore, this vectored approach holds promises in the treatment and prevention of a chronic disease like HIV infection. Here, we provide an overview of HIV genetic diversity, AAV vectorology, and anti-HIV bnAbs and summarize the promises and challenges of the application of AAV in the delivery of bnAbs for HIV prevention and therapy.

Background: Despite intense efforts, AIDS is difficult to tackle by current anti-retroviral therapy (ART) due to its side effects; therefore, there is an urgent need to discover potential, multitarget and low-cost anti-HIV compounds. Objective: We have shown that few phytocompounds can potentially inhibit the prime targets of HIV namely GP120 envelope protein, reverse transcriptase, protease, integrase and ribonulcease. In this study, top ranked prioritized compounds were subjected to Molecular Dynamics (MD) simulation in order to study the conformational dynamics and integrity of crucial interaction in the receptor sites. Methods: The system was built for selected protein-ligand complex using TIP3P water model and OPLS_2005 force field. Trajectories were recorded up to 20 ns simulation time in Desmond module of Schrödinger software. Results: As a result of a comprehensive analysis of molecular properties and dynamics of the complexes, it has been concluded that Chebulic acid, Curcumin and Mulberroside C could be developed as envelope glycoprotein GP120 inhibitor, reverse transcriptase inhibitor and protease inhibitor respectively. However, the fluctuation of Chebulic acid with respect to integrase and ribonuclease protein was higher during the simulation. Conclusion: These findings can aid in the designing of the structural properties for more effective anti-HIV compounds against the given targets.