One of the less-discussed factors that influences susceptibility to HIV infection is immune activation, which is interlinked with the availability of potential target cells for the virus. Several recent papers and a poster presentation at CROI 2014 shed additional light on this topic. In an open access review published in Retrovirology last November, Catherine Card and colleagues provide an overview of the science, focusing particularly on data generated by their studies of HIV risk factors among female sex workers in the Pumwani district of Nairobi, Kenya. This work has identified lower levels of immune activation—described as immune quiescence—as protective against HIV acquisition, and implicated specific polymorphisms in the interferon regulatory factor 1 (IRF-1) gene as contributing to the phenomenon. The same research group also published a study in the Journal of Infectious Diseases in January reporting that long-term (>1 year) involvement in sex work is associated with reduced mucosal immune activation, perhaps as a result of chronic exposure to diverse foreign antigens inducing regulatory, tolerance-like immune mechanisms. Based on these observations, a trial is about to be launched in Nairobi that will evaluate if daily administration of aspirin or hydroxychloroquine can reduce systemic and mucosal immune activation in HIV-negative women.
At CROI 2014, investigators involved in two large HIV prevention studies (the Partners in Prevention HSV/HIV Transmission Study and the Couples Observational Cohort Study) presented a case-control analysis that assessed the influence of a panel of different cytokines on transmission risk. Two cytokines linked with immune activation, IL-10 and IP-10, emerged as significantly associated, both in the partner acquiring HIV infection and the HIV-positive transmitting partner. The authors note that the results “suggest a potential parallel function of immune activation risk for HIV-1 susceptibility and infectiousness.”
Lastly, a paper from the research group of Julie Overbaugh published online in the Journal of Virology on March 12th looks at whether cellular immune activation markers and the number of CCR5-expressing HIV target cells affect the risk of superinfection with a second strain of HIV in a cohort of HIV-positive women. In this case, several markers of T cell activation were not associated with superinfection, but levels of CCR5-expressing HIV target cells were (although CCR5 is upregulated on T cells after activation, and so to some extent may also be considered an activation marker). The authors argue that target cell availability may be more important in governing HIV acquisition risk than immune activation per se (at least as measured by T cell activation markers), but it's unclear to what extent these results involving superinfection translate to HIV-negative individuals.
Taken together, these studies support the evaluation of strategies that promote immunological calm at sites of HIV exposure as potential prevention interventions (as has previously been suggested by Ashley Haase’s research in macaques). Catherine Card and colleagues caution that immune suppression should not be so profound as to blunt antiviral immune responses in the mucosa, and argue that enhancing HIV-specific immunity with vaccines while dampening generalized immune activation are potentially complementary approaches to reducing HIV acquisition risk.
Update 3/19/14: Thanks to Nicolas Vabret on twitter for pointing out that a 2012 macaque study conducted by the laboratory of Jean-Marie Andrieu reported an unprecedented degree of protection against an SIV challenge using a novel vaccine strategy that induced virus-specific regulatory CD8 T cell responses. The paper is available open access in the journal Cell Reports. This finding suggests that HIV-specific immune regulation, and not only generalized anti-activation approaches, could play a role in protection against HIV infection. My understanding is that there are plans to try and repeat the macaque experiment prior to considering advancing the approach into humans.
Retrovirology. 2013 Nov 20;10(1):141. [Epub ahead of print]
Card CM, Ball TB, Fowke KR.
Aberrant immune activation is a strong correlate of HIV disease progression, but little is known about how immune activation alters susceptibility to HIV infection. Susceptibility to HIV infection varies between individuals, but the immunological determinants of HIV transmission are not well understood. Here, we present evidence from studies of HIV transmission in the context of clinical trials and HIV-exposed seronegative (HESN) cohorts that implicates elevated immune activation as a risk factor for acquiring HIV. We propose a model of protection from infection based on a phenotype of low baseline immune activation referred to as immune quiescence. Immune quiescence is evidenced by reduced expression of T cell activation markers, low levels of generalized gene transcription and low levels of proinflammatory cytokine and chemokine production in the periphery and genital mucosa of HESN. Since HIV preferentially replicates in activated CD4+ T cells, immune quiescence may protect against infection by limiting HIV target cell availability. Although the determinants of immune quiescence are unclear, several potential factors have been identified that may be involved in driving this phenotype. HESN were shown to have elevated proportions of regulatory T cells (Tregs), which are known to suppress T cell activation. Likewise, proteins involved in controlling inflammation in the genital tract have been found to be elevated in HESN. Furthermore, expression of interferon regulatory factor 1 (IRF-1) is reduced in HESN as a consequence of genetic polymorphisms and differential epigenetic regulation. Since IRF-1 is an important regulator of immune responses, it may play a role in maintaining immune quiescence. Based on this model, we propose a novel avenue for HIV prevention targeted based on reducing host mucosal immune activation.
J Infect Dis. 2014 Jan 12. [Epub ahead of print]
Lajoie J, Kimani M, Plummer FA, Nyamiobo F, Kaul R, Kimani J, Fowke KR.
Background. Unprotected intercourse and seminal discharge are powerful activators of the mucosal immune system and are an important risk factors for HIV transmission. This study was designed to determine if female sex work is associated with changes in the mucosal immunity.
Methods. Cervico vaginal lavage and plasma from 122 HIV uninfected FSW women (FSW) and 44 HIV uninfected low-risk non-FSW from the same socioeconomic district of Nairobi were analyzed for evidence of immune activation (IA). The cervico-mononuclear cells (CMC) were analyzed for cellular activation by flow cytometry.
Results. Lower IA was observed in the FSW compared to the low-risk as demonstrated by the lower level of MIP-3α (p<0.001), ITAC (p<0.001), MIG (p.0001), IL-1α (p<0.001), IL-1β (p<0.001), IL-1Rα (p=0.0002), IL-6 (p<0.001), IL-8 (p<0.001), IL-10 (p=0.01), IP-10 (p=0.0001), MDC (p<0.001), MIP-1α, (p<0.001), MIP-1β (p=0.005), MCP-1 (p=0.03) and TNF-α (p=0.006). Significant differences were noted as early as 1 year following initiation of sex work and increased with duration of sex work.
Conclusion. This study showed that sex work is associated with important changes in the mucosal immune system. By analyzing chemokine/cytokine levels and CMC activation, we observed a lower mucosal IA in HIV uninfected FSW compared to low-risk women.
Journal of Virology
Published ahead of print 12 March 2014, doi: 10.1128/JVI.00187-14
Catherine A. Blish1,2#, Ozge C. Dogan1, Walter Jaoko3, R. Scott McClelland2,3,4,5, Kishorchandra Mandaliya6, Katherine Odem-Davis1, Barbra A. Richardson5,7,8 and Julie Overbaugh1
We performed a case-control study of women at risk of HIV-1 superinfection to understand the relationship between immune activation and HIV-1 acquisition. An increase in the frequency of HIV-1 target cells, but not in other markers of T cell activation, was associated with a 1.7-fold increase in the odds of superinfection. This suggests that HIV-1 acquisition risk is influenced more by the frequency of target cells than by the generalized level of immune activation.