VIRAL, IMMUNOLOGICAL AND HOST FACTORS ASSOCIATED WITH HIV-1 MULTIPLE INFECTION AND SUPERINFECTION IN A HIGH RISK FISHING COMMUNITY AND A COHORT OF FEMALE SEX WORKERS IN UGANDA

Lead Research Organisation: MRC/UVRI Uganda Research Unit on AIDS

Abstract

In order to understand the best immune responses that an HIV vaccine should induce in order to protect against infection there are different individuals who have been studies such as those who are exposed to the HIV but remain un infected and others who have the virus but remain disease free for many years. There is also another group of individuals who could be studied to understand better protective immune responses. These are HIV-1 infected individuals who because of their sexual contacts get infected with another strain of viruses, what we call super infection. We want to study these individuals and compare them with others who have the same characteristics but do not get superinfected.
The study we propose to perform will compare the immune responses , virus characteristics and other host factors such as behaviour and exposure in those two groups.
We will follow participants participating in two high rosk cohorts in the fishing communities and in the sex worker cohort. We will follow a few individuals who are already infected but appear to continue with high risk behaviours and also follow all those who are identified as positive for the first time. Samples will be collected at three montly intervals. We will screen the sample at base line and one year. If an individual is found to be infected by more than one strain at one year but not at base line then this person is likely to have been superinfected during folowup. We weill then test other samples backwards up to a time this person is likely to have been superinfected. Immune responses, virus properties and other host factors before and after superinfection will be studies. If an individual is not superinfected at one year we will follow them to up two years. To look for superinfection we will use the most sensitive deep sequencing assay.

Technical Summary

A major challenge in the development of an HIV-1 vaccine is the poor understanding of immunological correlates of protection. Natural protective immune responses are being studied by looking at individuals who are highly exposed to HIV-1 but remain uninfected; those who control their viral loads early in infection; and those with different rates of HIV-1 progression. Another approach is to investigate the immune responses among individuals who have already established HIV-1 infection and then subsequently acquire other strains of HIV. This phenomenon, known as superinfection, can involve HIV strains belonging to the same or different clades (intra-clade and inter-clade super-infection, respectively). Lack of superinfection in HIV+ individuals with demonstrable continued exposure might also suggest some existing protective responses. Immunological and virological differences between the superinfected and non-superinfected individuals could help us to better understand protective immune responses and guide rational HIV vaccine design and development.
PURPOSE: To characterize the frequency of HIV-1 multiple infections and superinfections as well as the associated viral and host factors that may be relevant for HIV interventions and vaccine formulation.
OBJECTIVES:To a) establish the prevalence of multiple infection and the incidence of super-infection. b) To determine the timing of superinfection in relation to primary infection and development of immune responses. c) To compare the viral factors, immune responses, host genetic factors and markers of disease progression in individuals that acquire superinfection compared to those who don’t.
DESIGN: This is a prospective cohort study with a nested case-control study to follow up HIV-1 high risk individuals.
POPULATION: We will recruit participants from two high-risk populations: 1) the fisher folk cohort and selected landing sites along Lake Victoria in Masaka district 2) Female sex workers from the Good Health for Women Project (GHWP) in Kampala. Two strata will be jointly selected as follows: (a) a “prevalent stratum” of subjects who are HIV+ at baseline (b) an “incident” stratum of subjects HIV negative at baseline who later seroconvert.
LABORATORY METHODS: The earliest enrolment sample and that at one and two years will be screened for multiple infection using next generation deep sequencing in the gp41 and p24. In those found with superinfection at year one but absent at enrolment, we will perform a walk backwards analysis of samples to identify the time of superinfection. If no superinfection is identified at year one, the year 2 sample will be analyzed using a walk backwards analysis for detection of superinfection. This will enable the estimation of timing of superinfection. Immunological evaluations will be performed on stored samples taken before and after the time of the superinfection event using flowcytometry and tissue culture neutralization assays. We will also collect data using reproductive health, socio-demographic and risk behaviour questionnaires to assess the risk factors that predispose HIV+ individuals to superinfection.

Publications

10 25 50
 
Description NIH RO1
Amount $650,000 (USD)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 02/2015 
End 01/2020
 
Title Next Generation Sequencing-including metagenomics (not discovered by our group, but commercially available) 
Description The tool introduced is being used for next genration equencing to idetify new viruses and to sequence HIV 
Type Of Material Improvements to research infrastructure 
Year Produced 2016 
Provided To Others? Yes  
Impact Quicker generation of results and discovery of viruses 
 
Description Medical Informatics 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Training, publications, networking and additional funding
Collaborator Contribution Training, publications, networking and additional funding
Impact Training, publications, additional funding and networks
Start Year 2011
 
Description Superinfection studies 
Organisation Johns Hopkins University
Department School of Medicine Johns Hopkins
Country United States 
Sector Academic/University 
PI Contribution Provision of samples Clinical and epidemiological data
Collaborator Contribution Training in neutralization and screening for neutralization
Impact Training of staff and generation of results
Start Year 2012
 
Description Superinfection studies 
Organisation Johns Hopkins University
Country United States 
Sector Academic/University 
PI Contribution Provision of specimens for testing of our samples for superinfection. Provision of other clinical and epidemiological data
Collaborator Contribution Testing of samples for superinfection using the 454 deep sequencing
Impact Data has been generated on the frequency of HIV superinfection in one of our high risk cohorts. Training of our in data analyses
Start Year 2012
 
Description Superinfection studies 
Organisation National Institute of Virology Johannesburg
Country South Africa 
Sector Academic/University 
PI Contribution Provision of samples Clinical and epidemiological data
Collaborator Contribution Training in neutralization and screening for neutralization
Impact Training of staff and generation of results
Start Year 2012
 
Description Conference presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Health professionals
Results and Impact This was an international conference attended by many international delegates

Questions from audience
Year(s) Of Engagement Activity 2013
 
Description Policy makers 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Primary Audience Policymakers/politicians
Results and Impact Presentation of research findings to policy makers

There was interest in the possible importance of HIV subtypes in the current HIV epidemic
Year(s) Of Engagement Activity 2006