HIV-1 Virulence Appears More Potent Among Heterosexual Individuals

Are transmission bottlenecks to blame for the infection virulence of HIV-1 among individuals who engage in penile-vaginal vs anal intercourse?

A new study from a team at the Indian Institute of Science investigated the influence of transmission bottlenecks introduced via penile-vaginal intercourse compared with anal intercourse, with a statement on their findings noting that “variations in virus strains in different populations are associated with varying disease severity and treatment outcomes.”

They concluded that it is possible for transmission bottlenecks, or the viral particles that result in infection, to influence the evolution of viral fitness—also known as the strength of a virus—so that HIV-1 may lead to more severe disease among heterosexual individuals (HET) compared with men who have sex with men (MSM).

Using data from more than 340,000 individuals from China, Europe, the United Kingdom, the United States, and Australia followed for close to 40 years, the investigators considered their CD4 counts at seroconversion or HIV-1 diagnosis.

“While studies on small cohorts do support this notion, observations of the manifestations of this differential selection bias at the population level have been lacking,” the authors wrote. “Here, we examined reported early CD4 count measurements from approximately 340,000 HET and MSM, across geographies, ethnicities, and calendar years.”

There was an overall greater early reduction in CD4 measurements seen among HET compared with MSM (all P < .05):

• European Union/European Economic Area (EU/EEA), 2010-2018: 437 cells/mL in MSM vs 302 cells/mL in HET
• United States, 2006: 390 vs 314 cells/mL, respectively
• China, 2006: 368 vs 270 cells/mL
• Europe, 2002: 426 vs 283 cells/mL
• United Kingdom, 1990: 331 vs 230 cells/mL
• Europe and Australia, 1979-2000: 616 vs 592 cells/mL

In addition, these early reductions to lower CD4 counts were associated with a greater prevalence of progression to AIDS among HET vs MSM, at approximately 87% vs close to 68% (P < 10−4; Cohen’s d, ds = 0.36). According to the authors, this result “reflects the more severe disease caused by transmitter/founder strains in HET than MSM at the population level,” and multivariable regression analysis (timing of transmission, diagnosis delay, HIV-1 subtype, ethnicity, sex, age) did not change their finding.

Similar results were seen among HET and MSM with untreated HIV-1 infection in that for years 2006 to 2012 in China (P < 10−4), 2010 to 2018 in the EU/EEA(P < 10−4), 2006 to 2015 in the United States(P < 10−4), 1979 to 2000 in Europe and Australia (P < .05), 2002 to 2007 in Europe alone (P < 10−3), and 1990 to 1998 in the United Kingdom (P < 10−3), CD4 counts were lower across the board in HET compared with MSM.

However, no differences were seen in set point viral load (SPVL) between MSM and HET, respectively, for Europe and Australia and Europe alone, the 2 regions with such data available:

• Europe and Australia: 4.43 vs 4.49 log10 copies/mL
• Europe: 4.86 vs 4.76 log10 copies/mL

The authors noted that their findings may be due to different risk groups having different predominant modes of transmission, so that transmitter/founder strains of HIV-1 “directly affected by the bottlenecks, may have evolved differently in the different groups.”

They also note the importance of a theory on HIV-1 evolution at the population level: Our bodies may use SPVL to maximize virus transmission, such that “an intermediate SPVL has been argued, supported by data, to maximize transmission, striking a balance between increasing transmissibility and decreasing host survival with increasing SVPL.”

Areas for future investigation, they conclude, are differential selection bias in MSM and HET and the influence of mixing between MSM and HET (eg, how a strain circulating in MSM would behave if/when transmitted to HET).

Reference

James A, Dixit NM. Transmitted HIV-1 is more virulent in heterosexual individuals than men-who-have-sex-with-men. PLoS Pathog. Published online March 10, 2022. doi:10.1371/journal.ppat.1010319