Host Factors that Modulate Risk of Heterosexual HIV-1 Acquisition and Disease Progression Open Access
Connolly, Sarah (Spring 2020)
Abstract
The Human Immunodeficiency Virus (HIV-1) currently infects 37.9 million people and is responsible for a total of 32 million deaths since the first cases were reported in 1981. In the absence of a cure or preventive vaccine, highly effective antiretroviral therapy and public health approaches to prevent new infections are the best means for overcoming the epidemic. Understanding how various host factors like Fc-gamma receptor (FcgR) genotype, human leukocyte antigen (HLA) haplotype, and other sexually transmitted infections (STI) modulate the risk of HIV-1 acquisition can improve prevention strategies and identify targets for an HIV-1 vaccine.
Single-nucleotide polymorphisms at the FcgRIIA and FcgRIIIA loci result in distinct genetic variants with different binding affinities for IgG antibodies. We examined two heterosexual transmission cohorts with different subtypes of HIV-1, subtype A and subtype C, and found no associations between FcgR genotype and HIV-1 acquisition or disease progression.
In a cohort of serodiscordant Zambian couples, we explored how HIV-1 adapts to host HLA pressure across the entire subtype C proteome. We found that individuals infected by a virus where the proteins Pol or Vif were already adapted to their HLA alleles experienced higher viral loads and faster CD4 decline.
Finally, owing to the fact that STIs are a known risk factor for HIV-1 acquisition, we sought to understand sociodemographic and laboratory risk factors for the bacterial STIs chlamydia (CT) and gonorrhea (NG) in a population of Zambian women at high-risk for HIV-1 infection. Through multivariate logistic regression modeling, we identified and compared associations between CT and NG with city, age, literacy, education, unprotected sex, contraception, and co-infections with other STIs. We found that risk factors were different for CT and NG, and that signs and symptoms were not associated with either infection.
The human immune system is highly variable both within and between individuals, and co- infections by other pathogens add further complexity. HIV-1 is constantly engaged in a delicate balance with numerous host factors in order to evade immune detection and maximize survival. Characterizing these host factors provides insight that might enable humans to tip the balance in our favor.
Table of Contents
Abstract
Acknowledgements
Chapter I: Introduction................................................................................. 1
Introduction.......................................................................................... 1
Global HIV-1 Epidemiology....................................................................... 2
HIV Vaccine Trials................................................................................... 4
Strategy for Reducing Transmission in Heterosexual Couples.................................. 6
HIV Disease Progression............................................................................. 7
HIV Viral Characteristics & Life Cycle.......................................................... 8
Viral Attachment and DC-SIGN.................................................................. 9
Attachment via FcgRs............................................................................... 11
Diversity at the Human FcgR Locus............................................................... 13
Viral Entry............................................................................................ 15
Reverse Transcription............................................................................... 16
Integration............................................................................................. 18
Replication............................................................................................ 19
Assembly & Egress................................................................................. 20
Defensins............................................................................................. 22
MHC and CTL Escape.............................................................................. 24
Transmission of HLA-Adapted Virus............................................................. 26
Antibodies Against HIV-1.......................................................................... 28
Other Sexually Transmitted Infections as Risk Factors for HIV Acquisition............... 30
Summary.............................................................................................. 32
Chapter II: Fc-gamma receptor IIA and IIIA variants in two African cohorts: Lack of
consistent impact on heterosexual HIV acquisition, viral control, and disease progression............................................................................................... 33
Abstract............................................................................................... 34
Introduction.......................................................................................... 35
Methods.................................................................................................. 38
Results.................................................................................................. 44
Discussion............................................................................................ 48
Conclusion............................................................................................ 53
Acknowledgements................................................................................. 54
Table 1. Description of cohorts...................................................................... 55
Figure 1. Distribution of FcgRIIA and FcgRIIIA genotypes across
country, sex, and HIV status ....................................................................... 56
Table 2. Odds of exposure to high affinity FcgRs among HIV+ cases
and HIV- controls.................................................................................... 57
Figure 2. Kaplan-Meier survival analysis for time-to-infection (TTI)
in Rwanda and Zambia by FcgR locus............................................................ 59
Figure 3. Kaplan-Meier survival analysis and adjusted Cox
proportional hazard regression models for time-to-infection (TTI)
based on exposure to high affinity FcgRs......................................................... 60
Figure 4. Comparing set point viral load and FcgR genotype
by country.............................................................................................. 62
Table 3. Adjusted linear regression model of set point viral load
based on exposure to high affinity FcgRs......................................................... 63
Figure 5. Kaplan-Meier survival analysis for CD4 decline from
time of infection to < 350 cells/μl by country and FcgR genotype............................ 65
Figure 6. Adjusted Cox proportional hazard regression models
for CD4 decline to < 350 cells/μl by exposure level to high affinity
FcgRs alleles.......................................................................................... 66
Supplemental Figure 1............................................................................... 67
Supplemental Figure 2............................................................................... 68
Supplemental Figure 3................................................................................ 69
References........................................................................................... 70
Chapter III: HLA-associated preadaptation in HIV Vif is associated with higher set point
viral load and faster CD4 decline in Zambian transmission pairs................................. 78
Abstract............................................................................................... 79
Introduction........................................................................................... 80
Methods.................................................................................................. 82
Results.................................................................................................. 86
Discussion............................................................................................ 89
Figure 1. HLA-associated sites by protein........................................................ 93
Figure 2. Heterologous vs. autologous adaptation............................................... 94
Figure 3. Longitudinal adaptation by protein..................................................... 95
Figure 4. Preadaptation vs. viral load by protein.................................................. 96
Figure 5: Preadaptation and CD4 decline to < 250 cells/μl..................................... 97
References........................................................................................... 98
Chapter IV: Sociodemographic factors and STIs associated with Chlamydia trachomatis
and Neisseria gonorrhoeae infection in Zambian female sex workers and single mothers... 105
Abstract............................................................................................... 106
Introduction........................................................................................... 107
Methods.................................................................................................. 108
Results.................................................................................................. 112
Discussion.............................................................................................. 116
Acknowledgements..................................................................................... 119
Table 1. Prevalence of signs and IVP by CT and/or NG status and city,
Zambian HRW, 2016................................................................................ 120
Table 2. Prevalence of lab results by CT and/or NG status and city,
Zambian HRW, 2016................................................................................ 121
Table 3. Prevalence of demographic factors and risk behaviors by
CT and/or NG status and city, Zambian HRW, 2016........................................... 122
Table 4. Logistic regression models of factors associated with CT,
Zambian HRW, 2016................................................................................ 123
Table 5. Logistic regression models of factors associated with NG,
Zambian HRW, 2016................................................................................ 124
References.............................................................................................. 125
Chapter V: Discussion.................................................................................. 131
HIV is a Game of Cat and Mouse................................................................. 131
Lessons on FcgRs, Preadaptation, and STIs..................................................... 135
Is Ending the Epidemic Possible?.................................................................. 139
Summary.................................................................................................. 141
References for Introduction and Discussion........................................................... 142
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