Latest research highlights: Early CD8 inhibit HIV, recognition of HIV by NK cellsis mediated by IgG, review of immune dysfunction during HIV infection and latest data on IL-10 contributes to it, size of Th17 compartment predicts viral load
Using samples from subjects in the CHAVI 001 acute infection cohort, Freel, Tomaras et al. (J Virol, PMID 22514337) found that transmitted variants are inhibited by CD8+ responses very early after infection. By adding CD8+ T cells to transwell cultures, they showed that protection is mediated by cytokines and other soluble factors released by lymphocytes in response to viral peptides from gag, env and nef (responses to nef were found in all 11 tested subjects). During acute viremia, both autologous and heterologous viruses elicit these responses, but when the virus load goes down, the cells start responding only to autologous peptides. The virus, however, escapes these CD8+ responses within 6 months.
While it’s been observed that NK cells from infected people can recognize HIV peptides, the mechanism responsible for specificity is not known. Thobakgale, Altfeld et al. (J Virol, PMID 22496218) now show that the recognition is mediated by IgGs to viral proteins. Accordingly, they see that NK responses to HIV peptides are absent in acute infection and develop during the first year, correlating with appearance of antibodies to env and nef.
The damage that HIV does to the immune system goes beyond direct killing of memory lymphocytes. This fact is especially evident in the lack of complete immune reconstitution in patients on effective HAART. Zeng, Haase, and Schacker (Trends Immunol, PMID 22613276) review the current understanding of the effects of HIV infection on secondary lymphoid tissue. Viral replication leads to chronic immune activation, which leads to pathologic changes in lymph nodes, both in B follicles and in the T cell zone. Collagen deposition damages fibroblastic reticular cell networks, a crucial part of the microenvironment in the lymph node, responsible for storing and presenting IL-7 to lymphocytes. The authors describe new therapies that aim to improve immune reconstitution, either by providing exogenous IL-7 or by inhibiting fibrosis.
Immune dysfunction during chronic HIV infection is also the topic of the paper by Kwon, Kaufmann et al. (J Virol, PMID 22496237). They show that in HIV-infected people Tregs inhibit HIV-specific CD4 responses through IL-10 cytokine. Interestingly, Tregs don’t produce IL-10 themselves, but stimulate CD14+ monocytes to produce more IL-10 and less TNF-alpha. Treg stimulation of monocytes appears to require direct cell-to-cell contact. Blockade of IL-10 signaling pathway in infected people significantly improves T cell function and may be helpful for developing new HIV treatment or elimination strategies.
We know that MHC alleles can be either protective or make the person more susceptible to AIDS. But it is not well understood how the state of the immune system before HIV infection affects either acquisition or disease progression. This information, however, is critical for development of intervention strategies. Hartigan-O’Connor, McCune et al. (Sci Trans Med, direct link) show that in rhesus macaques the ratio of Th17/Treg cell compartment before infection inversely correlates with viral loads after infection with SIVmac251. Higher percentage of Th17 cells before infection also predicts more polyfunctional CD4 T cell responses to SIV.