Elite control of HIV and SIV infection
Small percentages of humans infected with HIV-1 and macaques infected with SIV spontaneously control the virus without the aid of antiretroviral drugs. By far the best predictor of an individual's ability to control the virus lies in which major histocompatibility complex class I (MHC-I) genes they express. MHC-I molecules present virus-derived peptides to CD8 T cells. We are studying rhesus macaques that express the MHC-I allele Mamu-B*17, the expression of which is associated with enhanced viral control, including in individuals that control the virus to undetectable levels. We are investigating the CD8 T cell responses these animals make against the virus as well as the specific manner in which the virus evolves to evade the response. We have found that, in macaques that express Mamu-B*17, CD8 T cells predominantly target the viral Nef protein and the virus evolves in a manner that compromises specific Nef functions, rendering the virus unfit and possibly enabling greater viral control. Thus, we are using immunological, virological and genetic techniques to understand effective immunity.
Identification of latently infected cells
One of the greatest obstacles to a cure for HIV is its propensity to integrate into the host genome and lie latent in certain cell types, including resting CD4 T cells and macrophages. A critical step towards a cure would be to identify and kill these latently infected cells before the virus begins to replicate. We are using high throughput RNA sequencing (RNA-seq) to identify novel markers of these cells, without the need to induce replication. In particular, we have found that the SIV genome remains transcriptionally active during a latency-like state where minimal viral replication is detected. Interestingly, we have found that the antisense strand of the viral genome also is transcribed but only in a small number of genomic locations to produce novel, presumably non-coding RNAs. Together, these data suggest that therapies designed to target particular viral products might be effective at eliminating the viral reservoir.
Mechanisms of protection from pathogenic SIV provided by novel SIV vaccines
Though not viable for clinical translation live attenuated SIV vaccines can serve as ideal models to discover the types of immune responses an effective vaccine needs to induce. Working with colleagues at the University of Pennsylvania, we are investigating a novel attenuated SIV vaccine that contains a two amino acid deletion in the SIV Envelope cytoplasmic tail. This virus replicates well initially but is rapidly controlled by the host (Pigtail macaques). These animals are then protected from a variety of pathogenic SIV challenges. This protection occurs in the absence of neutralizing antibodies and appears to be T cell mediated. We are exploring the mechanisms by which T cells induced by this vaccine can control pathogenic SIV challenges. Specifically, we are focused on how this particular deletion alters the distribution of molecular components of the virologic and immunologic synapses, leading to reduced viral spread and enhanced antiviral T cell function.
Zika infection of nonhuman primates
We are collaborating with a large team of scientists at Tulane and beyond to develop and optimize a nonhuman primate model of Zika virus infection in macaques, including pregnant females as well as adult and infant non-pregnant animals. Our goals are to comprehensively assess the pathogenicity of Zika in these animals and to assess immunological responses to the virus that might be responsible for preventing both viral dissemination into neurological and reproductive tissues and preventing maternal to fetal viral infection.
