Although anal intercourse is a common mode of HIV-1 transmission, particularly for men who have sex with men, many fundamental and mechanistic questions remain. The long-term objective of this study is to understand the early events in HIV-1 rectal transmission and to gain new insights, which will potentially lead to new intervention strategies, including vaccines and topical microbicides optimized for rectal use. Studying HIV-1 vaginal transmission in the highly relevant SIV-rhesus macaque model has revealed important events critical for transmission, such as target cell availability, innate immune response, and inflammation at the portal of entry, all factors which play a key role in transmission. Because the anatomical/histological features and the physiological functions of vagina and cervix differ from the rectum, we hypothesize that the underlying mechanisms and timing of HIV-1 rectal transmission will significantly differ from those of vaginal-cervical transmission. Utilizing innovative approaches and an established conceptual framework from studies of vaginal transmission, we will test this hypothesis by investigating three specific aims: 1) determine the timing, location, spatial distribution and cell types of virus-infected cells at the portal of entry and in draining and distal lymphatic tissues;2) determine relationships between virus and susceptible target cells (CD4+ T cells, macrophages, and dendritic cells) and between virus-infected cells and the mucosal innate immune response in the rectum shortly after intra-rectal SIV inoculation, thereby determining whether changes in target-cell availability play a critical role in local expansion and systemic spread of infection;and 3) determine the spatial relationships and ratio of virus-specific CD8+ T effector cells (E) and virus-infected-target cells (T) at the portal of entry and in other tissue compartments to extent of control of virus replication, using a novel procedure combining in-situ tetramers and in-situ hybridization The proposed research is significant as it is expected to reveal important mechanisms underlying rectal transmission and potentially provide guidance for designing anti-HIV-1 vaccines and topical microbicides.

Public Health Relevance

Public Narrative The proposed studies are relevant to public health because unprotected anal intercourse is a common mode for HIV-1 transmission, especially in men who have sex with men. Thus, by studying for HIV-1 rectal transmission, new knowledge will be gained to aid HIV-1 vaccine and microbicide design and development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK087625-04
Application #
8310089
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Hamilton, Frank A
Project Start
2010-08-15
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$295,479
Indirect Cost
$71,316
Name
University of Nebraska Lincoln
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
555456995
City
Lincoln
State
NE
Country
United States
Zip Code
68588