Conversations with Narendra Dixit: Increased HIV-1 virulence in heterosexual populations compared with MSM.

Variations in virus strains in different populations are associated with varying disease severity and treatment outcomes. A study publishing March 10th in PLOS Pathogens by Ananthu James and Narendra Dixit at Indian Institute of Science, India suggests that HIV-1 is more virulent when transmitted through penile-vaginal intercourse than anal intercourse due to transmission bottlenecks.

Dr. Dixit discussed the study with SCINQ over email.

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What prompted you to undertake this study?

There were reports from studies on small patient cohorts indicating that the barrier to HIV transmission was different across modes of transmission and that this may lead to more or less fit viral genomes getting transmitted based on the mode. We reasoned that this should imply different severities of the infection caused by the transmitted genomes based on the mode of transmission. No studies had reported on these differences.  This prompted us to undertake our study.

In general, what are transmission bottlenecks? Do they occur with all types of infections?

Transmission bottlenecks are constraints or barriers that prevent pathogens from getting transmitted from one individual to another despite the opportunity to do so.  They do occur with most infections, although to varying extents.

How do the different routes of infection serve as transmission bottlenecks for HIV?

With HIV, the bottlenecks arise due to the physical barriers imposed by the mucosal tissues at the site of transmission as well as by the immune environment in the region.  Both these could be different across modes. 

Dr. Narendra Dixit.

How do you propose the bottlenecks affect evolutionary selection of HIV?

The current understanding is that the stronger the bottleneck, the fitter the viral genome would have to be for successful transmission.  Thus, while strong bottlenecks reduce the success rate of transmission, they would likely end up selecting for fitter strains.

In your discussion section, you list confounding factors that may influence the initial CD4+ levels during the early stages of infection, e.g. virulence. Which ones would you say are the most significant ones? Why?

We assessed several factors that we felt would independently influence the CD4+ levels early in infection. These included the age of the individuals at the time of infection, the delay between contracting the infection and its diagnosis, and so on. We found that none of these factors affected our inferences significantly. 

You mention the fact that there are theories suggesting that the virulence of HIV may be increasing, decreasing, or staying the same. Where do you think the research supports? Why?

This question – of the evolution of HIV virulence – is an area of investigation.  Our study does not address this question directly.  What it does is to argue that virulence evolution may to be looked at separately in groups that use different predominant modes of transmission and seem not to inter-mix much, like MSM and heterosexuals.  

What is the significance of your findings? Can you place them within the context of what is already known or theorized?

As I mentioned above, while the differences in the bottlenecks across modes of transmission had been recognized in small cohorts, their manifestation at the population level had not been shown.  Our study provides evidence of the clinical manifestation of the differences at the large-scale population level.  

Specifically, the difference plays out in early CD4 counts in MSM and heterosexuals, as we show in the paper.  We hypothesized that differences in the fitness of the transmitted strains would affect early CD4 counts. 

Further, we reasoned that the early CD4 counts would be significantly different between MSM and heterosexuals because they use modes of transmission with significant differences in the bottlenecks and also seem not to inter-mix much.  Our analysis found strong support for these hypotheses.

For more information about Dr. Dixit and his research, visit his lab page.

IMAGE CREDIT: Reconfirming the Traditional Model of HIV Particle Assembly. Gross L, PLoS Biology Vol. 4/12/2006, e445. doi:10.1371/journal.pbio.0040445

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