Association between latent proviral characteristics and immune activation in antiretrovirus-treated human immunodeficiency virus type 1-infected adults.
Generalized immune activation during HIV infection is associated with an increased risk of cardiovascular disease, neurocognitive disease, osteoporosis, metabolic disorders, and physical frailty. The mechanisms driving this immune activation are poorly understood, particularly for individuals effectively treated with antiretroviral medications. We hypothesized that viral characteristics such as sequence diversity may play a role in driving HIV-associated immune activation. We therefore sequenced proviral DNA isolated from peripheral blood mononuclear cells from HIV-infected individuals on fully suppressive antiretroviral therapy. We performed phylogenetic analyses, calculated viral diversity and divergence in the env and pol genes, and determined coreceptor tropism and the frequency of drug resistance mutations. Comprehensive immune profiling included quantification of immune cell subsets, plasma cytokine levels, and intracellular signaling responses in T cells, B cells, and monocytes. These antiretroviral therapy-treated HIV-infected individuals exhibited a wide range of diversity and divergence in both env and pol genes. However, proviral diversity and divergence in env and pol, coreceptor tropism, and the level of drug resistance did not significantly correlate with markers of immune activation. A clinical history of virologic failure was also not significantly associated with levels of immune activation, indicating that a history of virologic failure does not inexorably lead to increased immune activation as long as suppressive antiretroviral medications are provided. Overall, this study demonstrates that latent viral diversity is unlikely to be a major driver of persistent HIV-associated immune activation.


OBJECTIVE
Chronic immune activation, which is associated with cardiovascular disease, neurologic disease, and early aging, is likely to be a major driver of morbidity and mortality in HIV-infected individuals. Although treatment of HIV with antiretroviral medications decreases the level of immune activation, levels do not return to normal. The factors driving this persistent immune activation, particularly during effective treatment, are poorly understood. In this study, we investigated whether characteristics of the latent, integrated HIV provirus that persists during treatment are associated with immune activation. We found no relationship between latent viral characteristics and immune activation in treated individuals, indicating that qualities of the provirus are unlikely to be a major driver of persistent inflammation. We also found that individuals who had previously failed treatment but were currently effectively treated did not have significantly increased levels of immune activation, providing hope that past treatment failures do not have a lifelong "legacy" impact.
Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
Emily C
EC
Liang
Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
Lindsay
L
Sceats
Stanford Immunology, Stanford University School of Medicine, Stanford, California, USA.
Nicholas L
NL
Bayless
Stanford Immunology, Stanford University School of Medicine, Stanford, California, USA.
Dara M
DM
Strauss-Albee
Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
Jessica
J
Kubo
Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
Philip M
PM
Grant
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA.
David
D
Furman
Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
Manisha
M
Desai
Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
David A
DA
Katzenstein
Stanford Immunology, Stanford University School of Medicine, Stanford, California, USA Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, California, USA Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, USA.
Mark M
MM
Davis
Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
Andrew R
AR
Zolopa
Department of Medicine, Stanford University School of Medicine, Stanford, California, USA Stanford Immunology, Stanford University School of Medicine, Stanford, California, USA Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, California, USA cblish@stanford.edu.
Catherine A
CA
Blish
D000328:Adult; D000368:Aged; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D016000:Cluster Analysis; D015331:Cohort Studies; D004279:DNA, Viral / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification; D024882:Drug Resistance, Viral; D005260:Female; D014644:Genetic Variation; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D006801:Humans; D007111:Immunity, Cellular; D007963:Leukocytes, Mononuclear / Q000821:virology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010802:Phylogeny; D011446:Prospective Studies; D011533:Proviruses / Q000276:immunology*; D017422:Sequence Analysis, DNA; D056189:Viral Tropism; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics; D054302:pol Gene Products, Human Immunodeficiency Virus / Q000235:genetics
D044966:Anti-Retroviral Agents; D004279:DNA, Viral; D054299:env Gene Products, Human Immunodeficiency Virus; D054302:pol Gene Products, Human Immunodeficiency Virus