HIV protein mutation may explain long-term nonprogression

Edwin J. Bernard
Estimated reading time 2 minutes
This article is more than 22 years old.

A key mutation in one of HIV’s genes, viral protein R (vpr), may further explain why HIV disease does not progress in a small group of people known as long-term nonprogressors (LTNPs).

Vpr - the protein coded by the vpr gene - is a small soluble protein which is not needed for HIV to reproduce in CD4 cell cultures but appears to be very important for HIV to reproduce in macrophages. Vpr can induce CD4 cell death even when the cells are not HIV-infected, and is also poisonous to cell mitochondria which may be important in killing cells which are HIV-infected.

LTNPs are defined as having had HIV infection for seven years or longer with no history of HIV-related symptoms, no exposure to antiretrovirals, and a preserved immune function (i.e. a CD4 count within the normal reference range). There have been many theories put forward as why LTNPs appear to thwart HIV, and these latest findings add a further, important piece to the puzzle.

Glossary

protein

A substance which forms the structure of most cells and enzymes.

long-term non-progressor

An HIV-infected person who remains free of AIDS symptoms (such as immune system decline or opportunistic diseases) for an unusually long period of time in the absence of treatment. These individuals typically have strong CD8+ T-cell responses, minimal lymph node damage and a relatively low viral load. About 10% of HIV-positive people seem to be long-term non-progressors. Most, but not all, are elite (or HIV) controllers. 

genes

Genes are instruction manuals for our bodies. They determine characteristics like our eye and hair colour. Every human has a set of around 20,000 genes. We get one copy of each gene from each of our parents. Genes can also play a part in our health and may affect our risk of developing some health condition.

mitochondria

Structures in cells that are the sites of the cell’s energy production.

naive

In HIV, an individual who is ‘treatment naive’ has never taken anti-HIV treatment before.

In the May 15th issue of the Journal of Clinical Investigation, Andrew Badley and colleagues from the Mayo Clinic in Rochester, Minnesota, found that eight out 10 LTNPs (80%) had the vpr mutation R77Q in their HIV, whereas the mutation was found in the HIV of only five out of 15 (33%) HIV-positive, antiretroviral-naïve individuals with a CD4 count below 500 cells/mm3; a difference which they found to be highly statistically significant. They went on to demonstrate in cell cultures and in mice that a form of Vpr including this mutation results in less apoptosis (programmed cell death) than an otherwise identical protein without the mutation.

As well as confirming that a particular region of vpr plays a significant role in the depletion of CD4-cells that characterises HIV disease, the authors suggest that this discovery may open the way to new treatments.

An accompanying commentary by Catherine Brenner and Guido Kroemer observes that HIV protease inhibitors have already been shown to interfere with the effects of the Vpr protein on mitochondria. These new findings may therefore help explain the observation that protease inhibitors can sustain CD4 counts even when viral load is high and drug resistance is present. The mutant Vpr may also be able to suppress the ability of non-mutant Vpr proteins to cause damage to the immune system, and so drugs targeted at non-mutant strains might form the basis of a treatment strategy.

Further information on this website

Long Term Survival

Targetting Other HIV Genes

References

Brenner C et al. The mitochondriotoxic domain of Vpr determines HIV-1 virulence (commentary). Journal of Clinical Investigation, 111: 1455-1457, 2003.

Lum JL et al. Vpr R77Q is associated with long-term nongressive HIV infection and impaired induction of apoptosis. Journal of Clinical Investigation, 111: 1547-1554, 2003.

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