A couple of nice papers published recently on the mechanisms by which HIV infection causes AIDS. The first concerns the possible role of bystander apoptosis induction in HIV infection and its role in disease progression. It has become evident that the process is not as simple as previously thought:
HIV-1 Induced Bystander Apoptosis. (2012) Viruses 4(11): 3020-3043; doi:10.3390/v4113020
Apoptosis of uninfected bystander cells is a key element of HIV pathogenesis and believed to be the driving force behind the selective depletion of CD4+ T cells leading to immunodeficiency. While several viral proteins have been implicated in this process the complex interaction between Env glycoprotein expressed on the surface of infected cells and the receptor and co-receptor expressing bystander cells has been proposed as a major mechanism. HIV-1 utilizes CD4 as the primary receptor for entry into cells; however, it is the viral co-receptor usage that greatly influences CD4 decline and progression to AIDS. This phenomenon is relatively simple for X4 viruses, which arise later during the course of the disease, are considered to be highly fusogenic, and cause a rapid CD4+ T cell decline. However, in contrast, R5 viruses in general have a greater transmissibility, are encountered early during the disease and have a lesser pathogenic potential than the former. The above generalization gets complicated in numerous situations where R5 viruses persist throughout the disease and are capable of causing a rigorous CD4+ T cell decline. This review will discuss the multiple factors that are reported to influence HIV induced bystander apoptosis and pathogenesis including Env glycoprotein phenotype, virus tropism, disease stage, co-receptor expression on CD4+ T cells, immune activation and therapies targeting the viral envelope.
The second paper discusses the possibilites for new drugs which fight HIV infection in more subtle ways than simply blocking enzyes:
Back to the future: revisiting HIV-1 lethal mutagenesis. Trends Microbiol. 26 November 2012, doi: 10.1016/j.tim.2012.10.006
The concept of eliminating HIV-1 infectivity by elevating the viral mutation rate was first proposed over a decade ago, even though the general concept had been conceived earlier for RNA viruses. Lethal mutagenesis was originally viewed as a novel chemotherapeutic approach for treating HIV-1 infection in which use of a viral mutagen would over multiple rounds of replication lead to the lethal accumulation of mutations, rendering the virus population non infectious – known as the slow mutation accumulation model. There have been limitations in obtaining good efficacy data with drug leads, leaving some doubt on clinical translation. More recent studies of the apolipoprotein B mRNA editing complex 3 (APOBEC3) proteins as well as new progress in the use of nucleoside analogs for inducing lethal mutagenesis have helped to refocus attention on rapid induction of HIV-1 lethal mutagenesis in a single or limited number of replication cycles leading to a rapid mutation accumulation model.
This is all good stuff, but it’s frustrating that after all these years we still don’t have a better picture of how HIV causes AIDS – and how to stop it.