Symposium on Nonhuman Primate Models for AIDS, November 2013
Highlights from the 31st Annual Symposium on Nonhuman Primate Models for AIDS held on 3–6 November 2013, in Atlanta, Georgia (www.yerkes.emory.edu/aidsconf/). The symposium was divided into six sessions with 54 oral presentations and 83 poster presentations. Louis Picker was the keynote speaker and Beatrice Hahn made a special presentation. Here we report on five presentations organized around two themes.
- INF-alpha pathways have a role in both innate antiviral responses and modulation of adaptive immunity during SIV/HIV pathogenesis.
- Stages of the menstrual cycle affect vaginal SIV transmission and pathogenesis in Pigtail and Rhesus Macaques. Comparison of the two species and adequacy for a model of HIV transmission in women.
INF-alpha pathways have a role in both innate antiviral responses and modulation of adaptive immunity during SIV/HIV pathogenesis.
The inhibitory role of type-I interferon on HIV replication/integration is known, but the factors involved in INF-mediated control of HIV infection are not yet well understood.
Beatrice Hahn’s team, at the University of Pennsylvania, conducted a longitudinal study of phenotypic characteristics of infectious viral strains in acutely infected individuals. By comparing transmitted founder (TF) viruses to viruses present in the same individuals during the chronic phase of the infection, they found that resistance to interferon alpha is a major determinant of TF viruses. Besides resistance to INF-alpha, TF viruses differed from chronic infection strains in several other ways:
- Increased binding to dendritic cells, with higher recruitment of T cells.
- Increased expression levels of Env proteins and increased number of spikes on the viral surface.
- Decreased Macrophage-tropism.
It is possible that these features give an early advantage to TF strains and disappear in chronic viruses under the selective pressures exerted by the immune system. These observations further support the hypothesis that innate immune responses, which are induced at sites of exposure such as mucosae, are a better obstacle to viral transmission from chronic individuals than from acutely infected individuals. Dr. Hahn’s group is planning to use this model to help identify IFN target genes involved in this innate anti-viral activity at mucosal sites and to expand the study to other types of INF. Overcoming viral mechanisms of INF resistance should be explored as an infection prevention tool along other modalities and could give vaccine developers new targets to improve protection by inducing a better innate immune response at sites of exposure.
IFN-induced pathways may also play a role in the control of disease progression post infection. Thomas Vanderford from the Yerkes Primate Center, reported on the effects of blocking the INF-alpha pathways with neutralizing anti-INF-alpha antibodies (AG-009 from Argos Therapeutics) prior to SIV infection in the Rhesus Macaque (RM). INF-blocked animals showed marginally higher viral loads than controls and progressed in greater number to AIDS over a one year period. The overall levels of lymphocytes and monocytes were unaffected but fine modulation of immune cell subsets could be observed 2 to 4 weeks post-infection:
- The fraction of PD1+ and/or Ki67+ CD4 and CD8 T cells was lower in all infection stages.
- The frequency of Ki67+ B cells was lower during the chronic phase.
- NFkB pathways, TCR pathways and IL2R were transiently activated.
Blocked animals that did not progress to AIDS over the one year period, had higher level of PD1+ Ki67+ CD4 T cells and PD1+ CD8 T cells than blocked animals who developed the disease, suggesting that INF-alphas control the activation of PD1+ T cell subset populations during infection.
Stages of the menstrual cycle affect vaginal SIV transmission and pathogenesis in Pigtail and Rhesus Macaques. Comparison of the two species and adequacy for a model of HIV transmission in women.
The single-celled columnar epithelium region of the cervix (transformation zone) has been hypothesized to be the major anatomical site of HIV infection after vaginal exposure in women. However, previous studies conducted in Thomas Hope’s group, at Northwestern University, using in vivo or explant models in several species including NHPs, revealed that the transformation zone is unlikely to be a major site of HIV entry as it is covered by a heavy mucus layer that can act as an effective barrier to the virus. In vivo NHP studies (1), showed that viral particles penetrate the squamous epithelium of the entire lower female genital tract (FGT). Here Dr. Hope presented RM studies making use of viral particles containing fluorescent viral constructs that can be detected with great specificity in the dissected tissues and cells harvested from animals after vaginal exposure. Surprisingly, the ovaries were found to be one of the hot spots for viral entry as 50% of the ovaries dissected contained infected cells (mainly CD4 T cells). The mechanisms by which the virus reaches the ovaries is not known and could involve more than simple diffusion; in any case, this reveals that the virus is able to move rapidly to the upper FGT. These unexpected findings illustrate how, to date, the mucosal sites of HIV transmission in the FGT are still not well understood and that studies to understand mucosal sites of transmission and protection and how these may vary during the menstrual cycle are warranted.
Two other groups reported on the validation of NHP models as tools to elucidate vaginal transmission at different stages of the menstrual cycle. Pigtail macaques (PTs) have been reported to be more susceptible to vaginal transmission of SIV and other STD than Rhesus macaques (RMs). Ellen Kersh, from the CDC, reported on a retrospective analysis of infection rates at time points in menstrual cycle in 46 PTs, which confirmed a seven fold higher risk of infection during high progesterone luteal phase than during the follicular phase in this species.
Ron Veazey’s group, from Tulane University, compared hormonal levels, mucosal thickness, anatomy, and cellular immunity from both species before and after SIV challenge at precisely timed days of the menstrual cycle. The two species showed strong differences in anatomic details and hormonal levels. Unlike RM’s, PT vaginas show strong similarities to humans during the luteal phase, with a much thinner vaginal epithelium during menses (d 0), but both species’ vaginal anatomies were alike during the follicular phase (d 14), with thick keratinized epithelia, which is also observed in women. The increased susceptibility of PTs to SIV infection was confirmed at the luteal stage (d 0), but SIV inoculation at d14 induced higher peak and VL set point in both species.
Detailed exploration of the female NHP genital tract environment can provide good models for observation of factors that may affect levels of infectivity in women, such as mechanical barriers, non-STD related inflammation, progesterone/estrogen ratios, immune suppression in vaginal epithelium (e.g., egg present with tolerance to paternal antigens), age-related changes (e.g., thickening of the vaginal wall at ‘middle’ age; thinning again at pre-menopause).
- Carias AM, McCoombe S, McRaven M, Anderson M, Galloway N, Vandergrift N, Fought AJ, Lurain J, Duplantis M, Veazey RS, Hope TJ. Defining the interaction of HIV-1 with the mucosal barriers of the female reproductive tract. J Virol. 2013 Nov; 87(21):11388-400.