Biology of HIV Transmission
HIV target cells in the female genital tract. Dendritic cells are key cells in initiating both adaptive and innate antiviral immunity. There has been considerable controversy regarding the role of productively infected dendritic cells (DC) in HIV transmission and we set out to determine the full range of SIV target cells in the female genital tract. These studies determined that all CD4+ cells in the genital mucosa; T cells, macrophages and dendritic cells (including intraepithelial Langerhans cells) become infected within 18 hours of intravaginal SIV inoculation and that virus disseminates rapidly from the genital tract to systemic lymphoid tissues. We have also shown that the genotype of the virus circulating in the blood maybe a recombinant variant between the virus that a person was exposed to and may not necessarily reflect the genotype of a transmitted virus.
In early simian immunodeficiency virus (SIV) and human immunodeficiency virus-1 (HIV-1) infections, gut-associated lymphatic tissue (GALT), the largest component of the lymphoid organ system, is a principal site of both virus production and depletion of primarily lamina propria memory CD4+ T cells; that is, CD4-expressing T cells that previously encountered antigens and microbes and homed to the lamina propria of GALT. In a recent paper we showed that peak virus production in gut tissues of SIV-infected rhesus macaques coincides with peak numbers of infected memory CD4+ T cells. Surprisingly, most of the initially infected memory cells were not, as expected activated but were instead immunophenotypically ‘resting’ cells that, unlike truly resting cells, but like the first cells mainly infected at other mucosal sites and peripheral lymph nodes are capable of supporting virus production. In addition to inducing immune activation and thereby providing activated CD4+ T-cell targets to sustain infection, virus production also triggered an immunopathologically limiting Fas–Fas-ligand-mediated apoptotic pathway in lamina propria CD4+ T cells, resulting in their preferential ablation. Thus, SIV exploits a large, resident population of resting memory CD4+ T cells in GALT to produce peak levels of virus that directly (through lytic infection) and indirectly (through apoptosis of infected and uninfected cells) deplete CD4+ T cells in the effector arm of GALT. The scale of this CD4+ T-cell depletion has adverse effects on the immune system of the host, underscoring the importance of developing countermeasures to SIV that are effective before infection of GALT.
Although a number of preclinical studies in macaques have been published demonstrating vaccine-mediated protection from intravenous SIV or SHIV challenge, there are very few studies that have achieved reproducible protection against intravaginal viral challenge. In non-human primate models of AIDS, live attenuated lentiviruses provide the most reliable protection from systemic and mucosal challenge with pathogenic SIV. Although live attenuated lentiviruses may never be used in humans due to safety concerns, understanding the nature of the protective immune mechanisms induced by live attenuated vaccines in primate models is thought to be critical for developing other vaccine approaches. Approximately 60% of rhesus macaques immunized with nonpathogenic SHIV89.6 are protected from the infection or clinical disease after intravaginal (IVAG) challenge with pathogenic SIVmac239 and that the route of immunization does not affect the efficacy of this vaccine approach. This is the highest level of protection ever reproducibly achieved in an intravaginal SIV challenge system. The protection in this model was associated with anti-viral CD8+ T cell responses and for the first time we showed that innate antiviral immune responses (IFN-alpha) were also associated with the vaccine-mediated protection. In fact, in chronic stages post-infection unregulated expression of IFN-gamma in lymphoid tissues is associated with uncontrolled viral replication due to the continuous recruitment of viral target cells to the sites of replication. In a further study of the same animals, we demonstrated that lymphoid tissues vaccinated-unprotected monkeys had significantly higher beta-chemokine mRNA expression levels and increased number of beta-chemokine positive cells compared to vaccinated-protected animals. Thus, despite considerable in-vitro evidence to the contrary, we found no evidence that beta-chemokines contributed to vaccine-mediated control of viral replication after intravaginal challenge with SIVmac239. Thus a successful HIV vaccine must generate robust specific and innate antiviral immunity and allow the recipient to make adaptive immune responses without the immune activation and inflammation that contributes to viral replication.
Depo-Provera is an injectable synthetic progestin that is widely used by women for hormonal contraception and its use has been associated with increased susceptibility to HIV transmission. To determine if Depo-Provera could affect the efficacy of an HIV vaccine designed to prevent HIV sexual transmission, we designed a preclinical study using our live-attenuated vaccine model. We found that the rate of protection following intravaginalSIVmac239 challenge was significantly lower and the acute post-challenge plasma vRNA levels significantly higher in Depo-Provera-treated/SHIV89.6 immunized monkeys compared to Depo-Provera-naive/SHIV89.6 immunized (SHIV) monkeys. Clearly progesterone treatment prior to intravaginal challenge with pathogenic virus can decrease the efficacy of a model “vaccine” in the primate model of HIV sexual transmission. This study indicates that care should be taken in designing and interpreting the results of preclinical primate vaccine studies that utilize progesterone pretreatment prior to intravaginal challenge with pathogenic virus. Further, Phase III HIV vaccine trial design should consider whether the use of exogenous progestins for contraception can decrease the efficacy of an HIV vaccine in women.
Fieni F, Stone M, Ma ZM, Dutra J, Fritts L, Miller CJ. Viral RNA levels and env variants in semen and tissues of mature male rhesus macaques infected with SIV by penile inoculation. PLoS One. 2013 Oct 11;8(10):e76367. doi: 10.1371/journal.pone.0076367. eCollection 2013. PubMed PMID: 24146859; PubMed Central PMCID: PMC3795772.
Carroll TD, Matzinger SR, Barry PA, McChesney MB, Fairman J, Miller CJ. Efficacy of influenza vaccination of elderly rhesus macaques is dramatically improved by addition of a cationic lipid/DNA adjuvant. J Infect Dis. 2014 Jan 1;209(1):24-33. doi: 10.1093/infdis/jit540. Epub 2013 Oct 17. PubMed PMID: 24141979; PubMed Central PMCID: PMC3864389.
McChesney MB, Miller CJ. New directions for HIV vaccine development from animal models. Curr Opin HIV AIDS. 2013 Sep;8(5):376-81. doi: 10.1097/COH.0b013e328363d3a2. Review. PubMed PMID: 23836045; PubMed Central PMCID: PMC4060591.
Asmuth DM, Ma ZM, Albanese A, Sandler NG, Devaraj S, Knight TH, Flynn NM, Yotter T, Garcia JC, Tsuchida E, Wu TT, Douek DC, Miller CJ. Oral serum-derived bovine immunoglobulin improves duodenal immune reconstitution and absorption function in patients with HIV enteropathy. AIDS. 2013 Sep 10;27(14):2207-17. doi: 10.1097/QAD.0b013e328362e54c. PubMed PMID: 23660579; PubMed Central PMCID: PMC3754419.
G. Franchini, M. Vaccari, C. Fenizia, Z.M. Ma, A. Hryniewicz, A. Boasso, M. Doster, CJ Miller, N. Lindegardh, J. Tarning, A. Landay, G.M. Shearer. Transient increase of interferon-stimulated genes and no clinical benefit by chloroquine treatment during acute SIV infection of macaques. AIDS Res Hum Retroviruses. 2013 Nov 19 [Epub ahead of print]
Cammock CE, Halnon NJ, Skoczylas J, Blanchard J, Bohm R, Miller CJ, Lai C, Krogstad, PA. Myocarditis, Disseminated Infection, and Early Viral Persistence Following Experimental Coxsackievirus B Infection of Cynomolgus Monkeys. PLoS ONE 8: e74569. 2013
Qureshi, M. Genescà, L. Fritts, M.B. McChesney 1, M. Robert-Guroff, C.J. Miller. Infection with host-range mutant adenovirus 5 suppresses innate immunity and induces systemic CD4+ T cell activation in rhesus macaques. Plos One, In press.
C.R. Kang, Y. Huang, C.J. Miller. A discrete-time survival model with random effect for designing and analyzing repeated low-dose challenge experiments Biostatistics (2014), pp. 1–16 doi:10.1093/biostatistics/kxu040 In Press
M. Genescà , CJ Miller, HIV-1 prevention using Live-attenuated vaccines. Encyclopedia of AIDS edited by D. Richman, M. Stevenson, and T. Hope. Springer. In Press. 2013.