EDCTP Alumni Network

Fostering excellence and collaboration in the next generation of researchers

Call Senior Fellowship (SF)
Programme EDCTP1
Start Date 2008-07-31
End Date 2010-07-30
Project Code TA.2007.40200.011
Status Completed

Title

Frequency and determinants of dual infection with different strains of HIV-1 in low- and high-risk populations in Uganda

Objectives

To evaluate the frequency and determinants of dual infection with different strains of HIV-1 in low- and high- risk populations in Uganda. This study had four major objectives and 1 minor: • Implement and validate novel sequence analysis methods developed at the Rega Institute (Belgium) for the detection of instances of co-infection and superinfection in longitudinally collected samples • Determine the clinical consequences of dual infection by comparing disease progression (viral loads and CD4+ counts) between those with and without dual infection • Determine the course of virologic recombination that occurs after dual infection • Determine the immunologic correlates of dual infection • Determine the prevalence of HIV-1 drug resistance among recently infected commercial sex workers.

Host Organisation

Institution Country
Medical Research Council Programme on AIDS - Uganda Virus Research Institute (MRC/UVRI) Uganda

Participants

Name Institution Country
Eric Arts Western Reserve University United States
Frances Gotch Imperial College London United Kingdom
Heiner Grosskurth Medical Research Council Programme on AIDS - Uganda Virus Research Institute (MRC/UVRI) Uganda
Pontiano Kaleebu Medical Research Council Programme on AIDS - Uganda Virus Research Institute (MRC/UVRI) Uganda
Philippe Lemey Katholieke Universiteit Leuven Belgium
Pietro Pala Medical Research Council Programme on AIDS - Uganda Virus Research Institute (MRC/UVRI) Uganda
Deogratius Ssemwanga Medical Research Council Programme on AIDS - Uganda Virus Research Institute (MRC/UVRI) Uganda
Annemie Vandamme Katholieke Universiteit Leuven Belgium
Carolyn Williamson University of Cape Town South Africa

Study Design

Prospective cohort study on determinants of dual infection with HIV strains

Sites

Kampala

Students Supervised

Type Name Title University Start Date End Date
Molecular Virology with Thesis Ssemwanga Deogratius PhD Makerere University 2008 2012

Results & Outcomes

Various methodologies have been optimised and used for the detection and confirmation of dual infection. The study was unable to determine the incidence of co-infection and superinfection but was able to show HIV-1 subtype distribution, multiple infections, sexual networks and partnership histories in Commercial Sex Workers in Kampala. The prevalence of transmitted drug resistance among newly infected commercial sex workers was done among 42 women that seroconverted in the high risk population. DNA sequencing work is in progress.

Publications

Ssemwanga D, Lyagoba F, Ndembi N, Mayanja BN, Larke N, Wang S, Baalwa J, Williamson C, Grosskurth H, Kaleebu P. Multiple HIV-1 infections with evidence of recombination in heterosexual partnerships in a low risk Rural Clinical Cohort in Uganda. Virology. 2011 Mar 1;411(1):113-31. Epub 2011 Jan 15.
Ndembi N, Hamers RL, Sigaloff KC, Lyagoba F, Magambo B, Nanteza B, Watera C, Kaleebu P, Rinke de Wit TF. Transmitted antiretroviral drug resistance among newly HIV-1 diagnosed young individuals in Kampala. AIDS. 2011 Apr 24;25(7):905-10
Ssemwanga D, Ndembi N, Lyagoba F, Bukenya J, Seeley J, Vandepitte J, Grosskurth H, Kaleebu P. HIV-1 subtype distribution, multiple infections, sexual networks and partnership histories in Commercial Sex Workers in Kampala, Uganda. AIDS Res Hum Retroviruses. 2012 Apr;28(4):357-65
Ssemwanga D, Ndembi N, Lyagoba F, Magambo B, Kapaata A, Bukenya J, Lubega GW, Bertagnolio S, Vandepitte J, Grosskurth H, Kaleebu P. Transmitted Antiretroviral Drug Resistance among drug-naïve Commercial Sex Workers with recent infection in Kampala, Uganda. Clin Infect Dis. 2012 May;54 Suppl 4:S339-42.

Current Organisation

Medical Research Council Programme on AIDS - Uganda Virus Research Institute (MRC/UVRI)

Students Supervised

Type Name Title University Start Date End Date
PhD Deogratius Ssemwanga HIV-1 Inter and Intra- Subtype Dual Infection: Prevalence in HIV-1 Infected Ugandans and its Relationship to Disease Stage and Progression

Publications

Authors:
DeMarino , C
Pleet , ML
Cowen , M
Barclay , RA
Akpamagbo , Y
Erickson , J
Ndembi , N
Charurat , M
Jumare , J
Kashanchi , F
Date:
0018-05-28
Journal:
Sci Rep.
Content:

To date, the most effective treatment of HIV-1 is a combination antiretroviral therapy (cART), which reduces viral replication and reverses pathology. We investigated the effect of cART (RT and protease inhibitors) on the content of extracellular vesicles (EVs) released from HIV-1-infected cells. We have previously shown that EVs contain non-coding HIV-1 RNA, which can elicit responses in recipient cells. In this manuscript, we show that TAR RNA levels demonstrate little change with the addition of cART treatment in cell lines, primary macrophages, and patient biofluids. We determined possible mechanisms involved in the selective packaging of HIV-1 RNA into EVs, specifically an increase in EV-associated hnRNP A2/B1. More recent experiments have shown that several other FDA-approved drugs have the ability to alter the content of exosomes released from HIV-1-infected cells. These findings on cART-altered EV content can also be applied to general viral inhibitors (interferons) which are used to treat other chronic infections. Additionally, we describe unique mechanisms of ESCRT pathway manipulation by antivirals, specifically the targeting of VPS4. Collectively, these data imply that, despite antiretroviral therapy, EVs containing viral products are continually released and may cause neurocognitive and immunological dysfunction.

Identifiers:
Authors:
Chaplin , B
Akanmu , AS
Inzaule , SC
Samuels , JO
Okonkwo , P
Ilesanmi , O
Adewole , IFA
Asadu , C
Khamofu , H
Mpazanje , R
Ndembi , N
Date:
2019-01-01
Journal:
J Antimicrob Chemother.
Content:

Background: Many lines of evidence point to HIV-1 subtype-specific differences in
the development of drug resistance mutations. While variation between subtype C
and others has been extensively explored, there has been less emphasis on
subtypes common to West Africa. We examined a previously described national
survey of pretreatment drug resistance in HIV-1-infected Nigerian children aged
<18 months, to explore the association between subtypes and patterns of
resistance.
Methods: Five hundred and forty-nine dried blood spots, from 15 early infant
diagnostic facilities in Nigeria, were amplified and HIV-1 polymerase was
sequenced. Four hundred and twenty-four were analysed for surveillance drug
resistance mutations (SDRMs). Associations between subtype and SDRMs were
evaluated by Fisher's exact test and logistic regression analysis, controlling
for geographical region and exposure.
Results: Using the sub-subtypes of HIV-1 G defined by Delatorre et al. (PLoS One
2014.
9: e98908) the most common subtypes were CRF02_AG (174, 41.0%), GWA-I (128,
30.2%), GWA-II (24, 5.7%), GCA (11, 2.6%), A (21, 5.0%) and CRF06_cpx (18, 4.2%).
One hundred and ninety infants (44.8%) had ≥1 NNRTI mutation, 92 infants (21.7%)
had ≥1 NRTI mutation and 6 infants (1.4%) had ≥1 PI mutation. By logistic
regression, 67N was more common in GWA-II/GCA than CRF02_AG (OR 12.0, P = 0.006),
as was 70R (OR 23.1, P = 0.007), 184I/V (OR 2.92, P = 0.020), the presence of ≥1
thymidine analogue mutation (TAM) (OR 3.87, P = 0.014), ≥1 type 2 TAM (OR 7.61,
P = 0.001) and ≥1 NRTI mutation (OR 3.26, P = 0.005).
Conclusions: This dataset reveals differences among SDRMs by subtype; in
particular, between the GWA-II and GCA subclades, compared with CRF02_AG and
GWA-I.

Identifiers:

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