Characterization of HIV-1 Superinfection in Cohabiting Heterosexual African Couples Público

Abstract

Human immunodeficiency virus type 1 (HIV-1), responsible for the AIDS pandemic, accounts for a profound global health burden, the heaviest of which is on Sub-Saharan Africa, in which most infections are genotypically identified as Subtype C. Despite major successes in public health interventions and anti-retroviral treatment, HIV-1 continues to accrue new infections worldwide, imploring an effective and cross-protective HIV-1 vaccine. To determine potential immunologic correlates of a protective HIV-1 vaccine, we investigated situations of natural re-infection, or superinfection, by HIV-1. Identifying factors affecting susceptibility to superinfection may elucidate protective factors that will be necessary to elicit in an HIV-1 vaccine.

Here we identified three cases of intrasubtype C superinfection in a cohort of twenty-two epidemiologically unlinked Zambian couples. We found that, despite longitudinal viral sequencing and phylogenetic analysis, all three cases of superinfection occurred from non-spousal partners within the first year of infection. This suggested that both sexual risk behavior and early immune responses might play a potential role in superinfection. Full-length envelope (env) sequencing data also surprisingly suggested very limited diversification of the env gene prior to superinfection, again supporting the hypothesis of limited neutralizing antibody (Nab) pressure on the virus to adapt, and a potential defect in the humoral response prior to superinfection.

We compared neutralizing and binding antibody responses within the first year of infection in the three superinfected individuals against 10 matched non-superinfected controls. Here we show that the superinfected group exhibited statistically significantly lower levels of autologous neutralizing antibodies to their founder/early viruses prior to superinfection as compared to Nab responses from non-superinfected controls at similar time points. Binding IgG antibodies to Subtype C gp120 and V1V2 proteins also trended towards being lower prior to superinfection. Together, this suggested that risk of superinfection might be highest during early infection, but that strong IgG antibodies (both neutralizing and potentially non-neutralizing) could play a role in protection from superinfection during this period. These data suggest that primary infection may elicit some protection against intrasubtype superinfection and lend hope towards the feasibility of a regionally-based HIV-1 vaccine in areas where a single subtype predominates.

Table of Contents

Table of Contents

Abstract Dedication Acknowledgements Chapter 1: Introduction. 1 Global Burden of HIV/AIDS. 1

Origin and Classification of HIV-1. 2

Viral Diversification. 4

HIV-1 Pathogenesis and Immunopathology. 5

Heterosexual Transmission of HIV-1. 7

Humoral Responses to HIV-1 Infection. 9

Identification of HIV-1 Superinfection. 12

Immune Responses in HIV-1 Superinfected Individuals. 15

Clinical Implications of HIV-1 Superinfection. 20

Summary. 21

Chapter 2: Timing and source of subtype-C HIV-1 superinfection in

the newly infected partner of Zambian couples with disparate viruses. 23

Table 1. Reported sexual activity of newly infected partner in
12 months post-primary infection. 49

Figure 1. Sequence and Highlighter Analysis of Longitudinal

Samples Provides Evidence for Superinfection. 50

Figure 2. Neighbor-joining tree of full-length SGA env sequences

for ZM282M. 51

Figure 3. Neighbor-joining tree representing full-length SGA env

sequences for ZM247F. 53

Figure 4. Neighbor-joining tree of full-length SGA env sequences

for ZM211M and ZM211F. 55

Figure 5. Neighbor-joining trees of SGA env and population gp41

sequences for the cohort. 56

Figure 6. Highlighter recombination plots of full-length env for

each individual who was superinfected. 57

Table S1. Demographic, clinical and behavioral data on 22

Zambian unlinked transmission pairs. 59

Chapter 3: HIV-1 subtype C superinfected individuals mount low

autologous neutralizing antibody response prior to intrasubtype

superinfection. 70

Figure 1. Homogeneity of early/founder env sequences prior to

superinfection in three intrasubtype C superinfected individuals. 98

Table 1. Seroconverters from ZEHRP cohort evaluated for

longitudinal autologous neutralization of initial variants. 100

Figure 2. Autologous neutralizing antibody responses to

early/founder Env in superinfected individuals during early infection. 101

Figure 3. Development of autologous neutralizing antibodies to

early/founder virus Env is slow or absent prior to superinfection. 103

Figure 4. Summary of neutralization titers to initial and

superinfecting variants. 104

Figure 5. Cross-neutralizing Breadth and Potency against HIV-1

Subtype C Env Reference Panel. 105

Figure 6. Plasma IgG binding antibody levels to purified subtype C

gp120 protein is also reduced in superinfected individuals. 106

Figure 7. Plasma IgA levels to purified subtype C gp120 protein

are highest in two of the three superinfected individuals. 108

Figure 8. Plasma binding antibodies to both clade B and C gp120

V1V2-loop proteins are absent in superinfected individuals prior to superinfection. 110

Figure S1. Radial neighbor-joining phylogenetic tree of full-length

env amplicon sequences. 112

Figure S2. Preferential neutralization of superinfecting virus Env

is observed in one case of early intrasubtype C superinfection. 113

Figure S3. Superinfecting viruses are sensitive to neutralization by

pooled subtype C plasma. 115

Figure S4. Limited heterologous neutralizing antibody breadth in

superinfected individuals prior to superinfection. 116

Chapter 4: Discussion. 125 Hope for an HIV-1 Vaccine. 125

Extracting Vaccinology Lessons from HIV-1 Superinfection Studies. 131

Summary. 138

Literature Cited of Introduction and Discussion. 140

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Health Sciences, Immunology Biology, Virology
Palavra-chave	dual infection subtype C HIV-1 HIV superinfection neutralizing antibody HIV-1
Committee Chair / Thesis Advisor	Hunter, Eric, Emory University
Committee Members	Grakoui, Arash, Emory University Derdeyn, Cynthia, Emory University Cooper, Max Dale, Emory University Allen, Susan A, Emory University Silvestri, Guido, Emory University

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