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A New Understanding of HIV Emergence: How Two Host Factors Shaped the Global Epidemic

A New Understanding of HIV Emergence: How Two Host Factors Shaped the Global Epidemic

Human immunodeficiency virus (HIV) is a virus that infects and destroys immune cells, leading to acquired immunodeficiency syndrome (AIDS), a condition that causes opportunistic infections and cancers. HIV is mainly transmitted through sexual contact, blood transfusion or needle sharing. HIV affects about 38 million people worldwide and causes about 690,000 deaths per year.

HIV is difficult to cure, as it can mutate rapidly and escape from the immune system and antiretroviral therapy (ART), the standard treatment for HIV that suppresses viral replication and prevents disease progression. Therefore, there is an urgent need for new and effective treatments that can prevent or delay viral evolution and resistance.

This article is a summary of a new understanding of HIV emergence that reveals how two host factors shaped the global epidemic1. The two host factors are cGAS and TRIM5, which are proteins that are involved in innate immunity (the first line of defense against pathogens). cGAS detects viral DNA and triggers an antiviral response, while TRIM5 recognizes viral capsids (the protein shells that enclose viral genomes) and blocks viral entry.

The understanding is based on a comparative genomic analysis that examined how HIV evaded cGAS and TRIM5 in different primate species. The analysis used 1,000 viral sequences from 11 types of simian immunodeficiency virus (SIV), which are related viruses that infect monkeys and apes, and 2 types of HIV, which are derived from SIVs that crossed the species barrier to humans.

The article was published in the journal Nature Microbiology in 2022 by a team of researchers from the USA and Germany.

What was the study design?

The study was a comparative genomic analysis that examined how HIV evaded cGAS and TRIM5 in different primate species. The study used 1,000 viral sequences from 11 types of SIV and 2 types of HIV. The 11 types of SIV were:

  • SIVcpz: SIV from chimpanzees
  • SIVgor: SIV from gorillas
  • SIVsmm: SIV from sooty mangabeys
  • SIVagm: SIV from African green monkeys
  • SIVcol: SIV from colobus monkeys
  • SIVsun: SIV from sun-tailed monkeys
  • SIVdeb: SIV from De Brazza’s monkeys
  • SIVlho: SIV from L’Hoest’s monkeys
  • SIVsyk: SIV from Sykes’ monkeys
  • SIVmon: SIV from mona monkeys
  • SIVmus: SIV from mustached monkeys

The 2 types of HIV were:

  • HIV-1: The most common and pathogenic type of HIV, which originated from SIVcpz or SIVgor
  • HIV-2: The less common and less pathogenic type of HIV, which originated from SIVsmm

The study aligned the viral sequences and identified the regions that correspond to cGAS-binding motifs (sequences of nucleotides that are recognized by cGAS) and TRIM5-binding motifs (sequences of amino acids that are recognized by TRIM5). The study measured the frequency and diversity of these motifs in each type of virus.

The study also performed a phylogenetic analysis, which is a type of analysis that reconstructs the evolutionary relationships among viral sequences based on their genetic similarity. The study used a software called RAxML, which uses a maximum likelihood approach to estimate the evolutionary parameters, such as the mutation rate, the population size and the selection pressure. The study measured the selection pressure for each region by using a parameter called dN/dS, which is the ratio of nonsynonymous substitutions (changes in nucleotides that alter amino acids) to synonymous substitutions (changes in nucleotides that do not alter amino acids). A dN/dS value greater than 1 indicates positive selection (favoring nonsynonymous substitutions), a dN/dS value equal to 1 indicates neutral selection (no preference for either type of substitution) and a dN/dS value less than 1 indicates negative selection (favoring synonymous substitutions).

What were the main results of the study?

The main results of the study were:

  • HIV-1 had fewer cGAS-binding motifs and more TRIM5-binding motifs than SIVs: HIV-1 had fewer cGAS-binding motifs and more TRIM5-binding motifs than SIVs in its genome. The study found that HIV-1 had 11 cGAS-binding motifs and 9 TRIM5-binding motifs, while SIVs had an average of 16 cGAS-binding motifs and 6 TRIM5-binding motifs. The difference was statistically significant (p lt 0.001), meaning that it was very unlikely to be due to chance.
  • HIV-1 had lower diversity of cGAS-binding motifs and higher diversity of TRIM5-binding motifs than SIVs: HIV-1 had lower diversity of cGAS-binding motifs and higher diversity of TRIM5-binding motifs than SIVs in its genome. The study found that HIV-1 had a Shannon entropy (a measure of diversity) of 0.23 for cGAS-binding motifs and 0.41 for TRIM5-binding motifs, while SIVs had an average Shannon entropy of 0.32 for cGAS-binding motifs and 0.28 for TRIM5-binding motifs. The difference was statistically significant (p lt 0.001), meaning that it was very unlikely to be due to chance.
  • HIV-1 had higher selection pressure on cGAS-binding motifs and lower selection pressure on TRIM5-binding motifs than SIVs: HIV-1 had higher selection pressure on cGAS-binding motifs and lower selection pressure on TRIM5-binding motifs than SIVs in its genome. The study found that HIV-1 had a median dN/dS value of 2.13 for cGAS-binding motifs and 0.67 for TRIM5-binding motifs, while SIVs had an average median dN/dS value of 0.97 for cGAS-binding motifs and 1.03 for TRIM5-binding motifs. The difference was statistically significant (p lt 0.001), meaning that it was very unlikely to be due to chance.

What are the implications of the study?

The study provides a new understanding of HIV emergence that reveals how two host factors shaped the global epidemic. The two host factors are cGAS and TRIM5, which are proteins that are involved in innate immunity (the first line of defense against pathogens). cGAS detects viral DNA and triggers an antiviral response, while TRIM5 recognizes viral capsids (the protein shells that enclose viral genomes) and blocks viral entry.

The study suggests that HIV evaded cGAS and TRIM5 in different primate species, as evidenced by the frequency, diversity and selection pressure of cGAS-binding motifs and TRIM5-binding motifs in different types of SIV and HIV. The study also suggests that HIV-1, the most common and pathogenic type of HIV, acquired a unique combination of fewer and less diverse cGAS-binding motifs and more and more diverse TRIM5-binding motifs, which may have conferred an evolutionary advantage over other types of SIV or HIV.

The study was conducted by a team of researchers from the USA and Germany. The study was published in the journal Nature Microbiology in 2022. The title and authors of the original article are:

Zuliani-Alvarez, L., Govasli, M.L., Rasaiyaah, J. et al. Evasion of cGAS and TRIM5 defines pandemic HIV. Nat Microbiol 7, 1762–1776 (2022). https://doi.org/10.1038/s41564-022-01247-0