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CHaPTEr 39 HIV and Acquired Immunodeficiency Syndrome 559

TABLE 39.4 Comparison of Immune responses That Influence VE in rV 144 Versus Past and
Ongoing Human Immunodeficiency Virus (HIV) Vaccine Trials
Immune response Identified
as a Correlate in rV144 responses in Non-rV144 Efficacy Trials responses in Vaccines in Current Development
Total IgG to V1V2 scaffold Lower in HVTN 505 compared with RV144 Higher titers in DNA/NYVAC/gp120 than RV144.
Correlates of protection in heterologous NHP challenge
studies with Ad26/Ad35 and Ad26/MVA studies
Serum IgA to gp120 (higher IgA = Higher IgA (including IgA to A1ConEnv) in HVTN 505, Administration of gp120 at onset of priming with NYVAC
lower VE) compared with RV144 and DNA/NYVAC markedly lowers serum IgA to gp120
DNA/MVA priming has lower IgA
IgG3 to V1V2 Lower in HVTN 505 and VAX003 than RV144 Under evaluation
ADCC activity Minimal ADCC in HVTN 505 ADCC correlates with protection in NHP using
Ad26 +/− trimeric gp120
High ADCC in DNA/MVA regimen
Tier 1 nAbs Higher frequency in RV144 compared with HVTN 505 Clade C regions under study
High avidity to gp120 Not measured in HVTN 505 program DNA/MVA containing regimens have high avidity. Other
Env IgG avidity with low IgA correlated with products under study
decreased risk of infection
CD4+ T cells with polyfunctional Different cytokine profile in HVTN 505 vs. RV144 DNA/NYVAC and Ad26/MVA increase prevalence and
response magnitude of Env specific CD4+ T cells

ADCC, antibody-dependent cellular cytotoxicity; Ig, immunoglobulin; nAbs, neutralizing antibodies.
Taken with permission from Corey et al. Sci Transl Med 2015 Oct 21;7(310):310rv7. doi:10.1126/ scitranslmed.aac7732.

trials in animals will lead to important clues for human study. Using viral vectors to place gene constructs within nuclear DNA
Illustration of clinical trials in antiretroviral-treated macaques that prevent HIV replication is the goal of such research. Arguably,
may be applied to humans in future by Byrareddy et al and the most advanced form of this genetic engineering to halt HIV
Nishimura et al. Monoclonal antibody specific for CD4 T cell replication is the zinc finger endonuclease approach to disrupt
surface integrin (α4β7) disrupts cellular trafficking of CD4 T specific genes necessary for the lifecycle of HIV. Adoptive transfer
cells with gastrointestinal tissue mucosal vascular addressin cell of autologous zinc finger–treated stem cells with infinite replica-
adhesion molecule (MAdCAM1). The CD4 T cell counts remained tion capacity may be an attractive future for individuals already
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steady, CD8 T cell immunity sharply increased, and HIV replica- infected with HIV. The extraordinary experiment of HLA-
tion became undetectable for up to 2 years. 41,42 As illustrated by matched and CCR5-δ35 deletion of hematopoietic stem cell
these HIV vaccine studies in animals, understanding the immune immunoreconstitution of an patient with HIV infection (“Berlin
correlates of vaccine efficacy is an absolute requirement for Man”) is a proof of concept of molecular and genetic engineering
judging the success of an HIV vaccine. to cure HIV infection, a technique totally impractical to the
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millions of patients with HIV infection worldwide. Nevertheless,
this “one in a million” chance experiment has demonstrated the
ON THE HOrIZON survival advantage of lymphocytes that cannot become infected
• Production of newer antiretroviral drugs, including those used for with HIV.
postexposure prophylaxis with greater specificity for interrupting events HIV, a type 1 retrovirus, contains merely 9 genes, but those
in the viral lifecycle and with fewer side effects for patients. 9 genes have so far thwarted all scientific efforts toward finding
• Investigation of new microbicidal drugs that can be safely applied a cure of its infection in humans. Optimism is warranted, however,
before exposure for protection against human immunodeficiency virus because of the enormous knowledge base the study of HIV has
(HIV) transfer.
• Development of preventive and therapeutic vaccines for HIV/acquired generated in understanding the many arms of innate and adaptive
immunodeficiency syndrome (AIDS) that induce strong viral neutralizing immunity protecting humans and the promise of a curative
antibody power and strong CD8 T-cell cytotoxic responses. treatment or vaccine for HIV. The HIV/AIDS pandemic has also
• Testing of gene construct-modified autologous hematopoietic stem brought the sobering realization that other new and potentially
cells capable of halting HIV replication. deadly pathogens may yet emerge to strike at humanity. Perhaps
no other disease has caused so much to be learned so fast. In
the developed world, HIV causes chronic infection, rather than
certain death, thanks, in large part, to the use of ARV drugs.
TRANSLATIONAL RESEARCH NEEDS More novel drugs are in development as a result of the new-found
AND CONCLUSIONS understanding of the molecular biology of HIV. HIV continues
to perplex and fascinate virologists and immunologists, and it
The quest for better ARV therapeutic agents continues, with the continues to teach humility to clinicians.
goal of greater selectivity and fewer side effects. However, the
eradication of HIV/AIDS can only be approached practically ACKNOWLEDGMENTS
with a preventive vaccine that elicits strong HIV-neutralizing
ability and generates a strong cytotoxic CD8 T-cell response Supported in part by NIH Grants HD052102, AI069536 AI36211,
specific for HIV antigens. The approach to cure with gene therapy and AI082978, and the Pediatric AIDS Fund of Texas Children’s
is perhaps the most sophisticated translational research venture. Hospital.