Capsid dependent evasion of innate immune sensing in macrophages distinguishes pandemic HIV-1(M) and non-pandemic HIV-1(O)

Jacques DA1,2, Hilditch L3, Rasaiyaah J3, James LC2 and Towers GJ3

  1. UNSW Sydney, NSW, 2052 Australia.
  2. MRC Laboratory of Molecular Biology, Cambridge, CB2 0QH, UK.
  3. University College London, London, WC1E 6BT, UK.

Transmission of simian immunodeficiency virus from great apes into humans has occurred on at least four separate occasions giving rise to the four distinct HlV1 groups: M, N, O, and P. The most common group, HIV1(M), was transmitted by chimpanzees and is the only group that has resulted in pandemic levels of human-to-human spread despite a similar time since introduction into human populations. The next most common group is HIV1(O), which originated from gorillas, and has resulted in significant spread (~100,000 human infections) yet has not reached the levels seen for HIV1(M) (~60,000,000 human infections) suggesting a reduced capacity to replicate in or transmit between humans. We have previously shown that the HIV1(M) capsid confers the ability to evade innate immune sensing in primary human macrophages. This evasion is dependent on the capsid’s ability to recruit host cofactors. When comparing HIV1(M) with HIV1(O), we find the HIV1(O) capsid to be less effective at evading innate immune triggering, with viral DNA activating the expression of interferon-stimulated genes. While this is analogous to HIV1(M) mutants that fail to engage host cofactors, HIV1(O) retains the ability to bind to CPSF6 and CypA demonstrating that binding per se is not responsible for the different phenotypes. Rather, the consequence of binding is altered. Phylogenetic comparison of HIV1(M) sequences and HIV1(O) CA sequences identified two key residues that split the M and O groups. Comparison of HIV1(M) and HIV1(O) CA crystal structures reveals that these two residues result in a less dynamic CA structure in HIV1(O), suggesting that it may not have the same allosteric capability as HIV1(M). This reduction in dynamics can be recapitulated in HIV1(M) through point mutation. We hypothesise that HIV1(O) capsids are less responsive to host cofactor interaction leading to premature reverse transcription, release of DNA, and innate immune triggering in macrophages. We further hypothesise that a reduction in the ability to infect these cells reduces the sexual transmissibility of HIV1(O) relative to HIV1(M), resulting in diminished pandemic potential.