December 2012

JBC thematic minireview series on HIV and the host

Just under 0.5 percent of the total human population carries the human immunodeficiency virus. That’s 34 million of us living with a virus for which there is not yet a vaccine. Ten percent of those infected are children, and the biggest disease burden is found in sub-Saharan Africa. Many of those infected will develop Acquired Immunodeficiency Syndrome. In 2010 alone, 1.8 million people died of AIDS-related illnesses.

Having jumped species into humans from chimpanzees in West Africa about 100 years ago, HIV has rapidly spread across the world, transmitted during sexual intercourse, unsterile injections and birth. Yet it was only in 1983 that HIV was discovered and linked to AIDS, a disease described only two years earlier. Since then, tremendous progress has been made into understanding the basic biology, epidemiology and evolution of the virus, and this has allowed us to develop effective pharmacological interventions, to diagnose new infections cheaply and easily, and even to develop a number of HIV vaccine candidates.

However, a number of challenges still lie ahead. Highly active antiretroviral therapy — one of the 20th century’s greatest achievements — can extend lifetime considerably, but the specter of drug resistance always looms. Based on past World Health Organization figures, 6.8 percent of HIV infections were drug resistant in low- to middle-income countries compared with more than 10 percent in high-income countries. Also, our most successful HIV vaccine trial in humans gained only modest results.

For these reasons and others, The Journal of Biological Chemistry decided to run a special minireview series about this exciting and important field of research, covering diverse topics spanning the replication cycle of HIV to help researchers continue the investigation of the basic biology of HIV in the hope of better understanding the enigmatic human pathogen.

“HIV remains a major global public health problem,” says Charles Samuel of the University of California, Santa Barbara, the convener of the series and a JBC associate editor. “Substantial progress has been made toward achieving a structural basis for understanding HIV virus interactions with host cells and the biochemical mechanisms by which HIV replicates. Hopefully this knowledge will fuel the development of more effective therapeutics and ultimately an effective vaccine.”

In his introduction to the review series, Samuel outlines the basic biology of HIV and the need to develop new treatment strategies, taking us through the steps of viral replication: entry, reverse transcription, integration, gene expression and assembly.

In their minireview, Robert Blumenthal and colleagues from the National Institutes of Health discuss the mechanism by which HIV enters its target host cell via viral glycoprotein-mediated membrane fusion, a process essential for HIV infection of target T cells, macrophages and dendritic cells and, hence, disease outcome. They focus their review on the dynamic process — what they call a “multistep dance macabre” — that occurs after viral receptor binding, which facilitates the transport of the bulky viral core through the cell membrane, and how we can study it using protein structure determination, lipid dye tracking and video microscopy.

Stuart F. J. Le Grice from the National Cancer Institute reviews the potential and past successes of HIV reverse transcriptase-targeted drug development. Reverse transcription in HIV — the enzymatic conversion of a single-stranded RNA genome into a double-stranded linear DNA copy that can be inserted into the host’s own genome — is an essential step in the HIV replication cycle. It is mediated by a multifunctional protein, RT, that mediates RNA binding, DNA synthesis and also RNase activity. Le Grice notes that many of the Food and Drug Administration’s approved anti-HIV drugs are RT inhibitors and that they are being developed as anal and vaginal microbicides to block virus transmission prophylactically.

The Dana–Farber Cancer Center’s Lavanya Krishnan and Alan Engelman document in their minireview the recent advances in the biochemistry of retroviral DNA genome integration, an obligate step in the virus life cycle and one that leads to the establishment of treatment refractory latent virus reservoirs in long-living host cells. Krishnan and Engelman take a structural perspective on how the viral nucleoprotein complex (specifically the HIV integrase enzyme) catalyses the integration reaction. They describe the growth in the field after the development of high-throughput small-molecule screening of integrase inhibitors.

Ronald Swanstrom and colleagues from the University of North Carolina–Chapel Hill detail the strategies by which HIV processes its single polyprotein (expressed from a genome-spanning open reading frame, a common strategy in small positive-sensed RNA viruses) into the enzymatic and structural machinery it needs to replicate, assemble and exit the cell. They concentrate on the protein-protein interaction domains necessary for the virus to carry these tasks out and discuss the potential for drugs that target these processes despite the rapid generation of antiviral resistance.

The dynamic interactions between HIV and host micro-RNAs are reviewed by Kuan-Teh Jeang and colleagues from the National Institute of Allergy and Infectious Disease. RNA interference, or RNAi, is an evolutionary conserved mechanism of post-transcriptional gene regulation mediated by the RNA-induced silencing complex known as RISC. Given its prominence in RNA regulation, it both targets and is a target of the RNA virus, HIV. This review focuses on the dynamic warfare between HIV and its host RNAi machinery. miRNAs have been shown to specifically target HIV’s RNA genome, and deregulated miRNAs are associated with HIV disease outcome. This minireview discusses how this virus could control these processes.

Finally, Reuben S. Harris and colleagues from the University of Minnesota discuss the role of innate restriction factors in defending against HIV. Restriction factors are molecules that negatively modulate viral replication. One necessary response to this is that viruses that infect humans have evolved means to combat these defenses. Harris and co-authors review this ancient evolutionary arms race with specific reference to the host-encoded APOBEC3 proteins, BST-2/Tetherin and SAMHD1 dNTP hydrolase. Comparing the HIV–human interaction to that of its primate cousin, simian immunodeficiency virus, with nonhuman primates, the authors outline how we could use this understanding to develop more effective HIV antivirals.
 

Photo of Connor BamfordConnor Bamford (connorggbamford@gmail.com) is a Ph.D. student at Queen’s University in Belfast, U.K.
 
 
 
 
 


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