Differential Expression of CREM/ICER Isoforms Is Associated with the Spontaneous Control of HIV Infection

ABSTRACTElite controllers (ECs) are a rare group of HIV seropositive individuals who are able to control viral replication without antiretroviral therapy. The mechanisms responsible for this phenotype, however, have not been fully elucidated. In this study, we examined CD4+T cell resistance to HIV in a cohort of elite controllers and explored transcriptional signatures associated with cellular resistance. We demonstrate that a subgroup of elite controllers possess CD4+T cells that are specifically resistant to R5-tropic HIV while remaining fully susceptible to X4-tropic and vesicular stomatitis virus G (VSV-G)-pseudotyped viruses. Transcriptome analysis revealed 17 genes that were differentially regulated in resistant elite controllers relative to healthy controls. Notably, the genes encoding macrophage inflammatory protein 1α (MIP-1α),CCL3andCCL3L1, were found to be upregulated. The MIP-1α, MIP-1β, and RANTES chemokines are natural ligands of CCR5 and are known to interfere with HIV replication. For three elite controllers, we observed increased production of MIP-1α and/or MIP-1β at the protein level. The supernatant from resistant EC cells contained MIP-1α and MIP-1β and was sufficient to confer R5-tropic resistance to susceptible CD4+T cells. Additionally, this effect was reversed by using inhibitory anti-MIP antibodies. These results suggest that the T cells of these particular elite controllers may be naturally resistant to HIV infection by blocking R5-tropic viral entry.IMPORTANCEHIV is a pandemic health problem, and the majority of seropositive individuals will eventually progress to AIDS unless antiretroviral therapy (ART) is administered. However, rare patients, termed elite controllers, have a natural ability to control HIV infection in the absence of ART, but the mechanisms by which they achieve this phenotype have not been fully explored. This paper identifies one mechanism that may contribute to this natural resistance: some elite controllers have CD4+T cells that produce high levels of MIP chemokines, which block R5-tropic HIV entry. This mechanism could potentially be exploited to achieve a therapeutic effect in other HIV-seropositive individuals.

Download Full-text

HIV-1 Env- and Vpu-Specific Antibody-Dependent Cellular Cytotoxicity Responses Associated with Elite Control of HIV

Journal of Virology ◽

10.1128/jvi.00700-17 ◽

2017 ◽

Vol 91 (18) ◽

Cited By ~ 27

Author(s):

Vijaya Madhavi ◽

Bruce D. Wines ◽

Janaki Amin ◽

Sean Emery ◽

Ester Lopez ◽

...

Keyword(s):

Immune Responses ◽

Hiv Infection ◽

Specific Antibody ◽

Cell Activation ◽

Nk Cell ◽

Enzyme Linked Immunosorbent Assay ◽

Cellular Cytotoxicity ◽

Antibody Dependent Cellular Cytotoxicity ◽

Elite Controllers ◽

Hiv Replication

ABSTRACT Studying HIV-infected individuals who control HIV replication (elite controllers [ECs]) enables exploration of effective anti-HIV immunity. HIV Env-specific and non-Env-specific antibody-dependent cellular cytotoxicity (ADCC) may contribute to protection from progressive HIV infection, but the evidence is limited. We recruited 22 ECs and matched them with 44 viremic subjects. HIV Env- and Vpu-specific ADCC responses in sera were studied using a novel enzyme-linked immunosorbent assay (ELISA)-based dimeric recombinant soluble FcγRIIIa (rsFcγRIIIa)-binding assay, surface plasmon resonance, antibody-dependent natural killer (NK) cell activation assays, and ADCC-mediated killing assays. ECs had higher levels of HIV Env-specific antibodies capable of binding FcγRIIIa, activating NK cells, and mediating granzyme B activity (all P < 0.01) than viremic subjects. ECs also had higher levels of antibodies against a C-terminal 13-mer Vpu peptide capable of mediating FcγRIIIa binding and NK cell activation than viremic subjects (both P < 0.05). Our data associate Env-specific and Vpu epitope-specific ADCC in effective immune responses against HIV among ECs. Our findings have implications for understanding the role of ADCC in HIV control. IMPORTANCE Understanding immune responses associated with elite control of HIV may aid the development of immunotherapeutic and vaccine strategies for controlling HIV infection. Env is a major HIV protein target of functional antibody responses that are heightened in ECs. Interestingly, EC antibodies also target Vpu, an accessory protein crucial to HIV, which degrades CD4 and antagonizes tetherin. Antibodies specific to Vpu are a common feature of the immune response of ECs that may prove to be of functional importance to the design of improved ADCC-based immunotherapy and preventative HIV vaccines.

Download Full-text

HIV and AIDS

10.2310/fm.1150 ◽

2018 ◽

Author(s):

Daniel R. Kuritzkes

Keyword(s):

Black Women ◽

Antiretroviral Therapy ◽

Hiv Infection ◽

Highly Active Antiretroviral Therapy ◽

The United States ◽

Hiv And Aids ◽

Hiv Care ◽

Hiv Replication ◽

Quarter Century ◽

Treatment And Prevention

In the quarter-century since the first report of AIDS in the United States, HIV infection has spread throughout the population, disproportionately affecting black women, Hispanic women, and men who have sex with men. The prognosis for persons infected with HIV has improved dramatically with the introduction and evolution of highly active antiretroviral therapy (HAART). The underlying principle of HAART is that a combination of potent antiretrovirals, each of which requires different mutations in the HIV genome for resistance to develop, can suppress replication sufficiently to prevent mutation and the emergence of resistance. The prospect that currently available antiretroviral therapy (ART) regimens may suppress HIV replication indefinitely provides the hope that infected patients will have life expectancies similar to those of age-matched uninfected individuals. For these patients, HIV care has shifted from an emphasis on treatment and prevention of the complications of HIV disease itself to a focus on suppression of HIV replication and management of short- and long-term complications of HIV, ART toxicities, and aging. This chapter describes the epidemiology, pathophysiology and pathogenesis, prevention, diagnosis, and management of acute and chronic HIV infection and AIDS, with figures and tables illustrating each chapter section. This review contains 9 highly rendered figures, 22 tables, and 248 references.

Download Full-text

HIV and AIDS

10.2310/im.1150 ◽

2017 ◽

Author(s):

Daniel R. Kuritzkes

Keyword(s):

Black Women ◽

Antiretroviral Therapy ◽

Hiv Infection ◽

Highly Active Antiretroviral Therapy ◽

The United States ◽

Hiv And Aids ◽

Hiv Care ◽

Hiv Replication ◽

Quarter Century ◽

Treatment And Prevention

In the quarter-century since the first report of AIDS in the United States, HIV infection has spread throughout the population, disproportionately affecting black women, Hispanic women, and men who have sex with men. The prognosis for persons infected with HIV has improved dramatically with the introduction and evolution of highly active antiretroviral therapy (HAART). The underlying principle of HAART is that a combination of potent antiretrovirals, each of which requires different mutations in the HIV genome for resistance to develop, can suppress replication sufficiently to prevent mutation and the emergence of resistance. The prospect that currently available antiretroviral therapy (ART) regimens may suppress HIV replication indefinitely provides the hope that infected patients will have life expectancies similar to those of age-matched uninfected individuals. For these patients, HIV care has shifted from an emphasis on treatment and prevention of the complications of HIV disease itself to a focus on suppression of HIV replication and management of short- and long-term complications of HIV, ART toxicities, and aging. This chapter describes the epidemiology, pathophysiology and pathogenesis, prevention, diagnosis, and management of acute and chronic HIV infection and AIDS, with figures and tables illustrating each chapter section. This review contains 9 highly rendered figures, 22 tables, and 248 references.

Download Full-text

Massive Release of CD9+ Microvesicles in Human Immunodeficiency Virus Infection, Regardless of Virologic Control

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa375 ◽

2020 ◽

Author(s):

Eva Poveda ◽

Andrés Tabernilla ◽

Wendy Fitzgerald ◽

Ángel Salgado-Barreira ◽

Marta Grandal ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Hiv Infection ◽

Elite Controllers ◽

Hiv Replication ◽

Mitochondrial Density ◽

Cellular Origin ◽

Immunodeficiency Virus ◽

Virologic Control ◽

Polymerase Chain

Abstract Background The role of extracellular vesicles (EVs) in human immunodeficiency virus (HIV) pathogenesis is unknown. We examine the cellular origin of plasma microvesicles (MVs), a type of ectocytosis-derived EV, the presence of mitochondria in MVs, and their relationship to circulating cell-free mitochondrial deoxyribonucleic acid (ccf-mtDNA) in HIV-infected patients and controls. Methods Five participant groups were defined: 30 antiretroviral therapy (ART)-naive; 30 ART-treated with nondetectable viremia; 30 elite controllers; 30 viremic controllers; and 30 HIV-uninfected controls. Microvesicles were quantified and characterized from plasma samples by flow cytometry. MitoTrackerDeepRed identified MVs containing mitochondria and ccf-mtDNA was quantified by real-time polymerase chain reaction. Results Microvesicle numbers were expanded at least 10-fold in all HIV-infected groups compared with controls. More than 79% were platelet-derived MVs. Proportions of MVs containing mitochondria (22.3% vs 41.6%) and MV mitochondrial density (706 vs 1346) were significantly lower among HIV-infected subjects than controls, lowest levels for those on ART. Microvesicle numbers correlated with ccf-mtDNA levels that were higher among HIV-infected patients. Conclusions A massive release of platelet-derived MVs occurs during HIV infection. Some MVs contain mitochondria, but their proportion and mitochondrial densities were lower in HIV infection than in controls. Platelet-derived MVs may be biomarkers of platelet activation, possibly reflecting pathogenesis even in absence of HIV replication.

Download Full-text

Liver disease, HIV and aging

Sexual Health ◽

10.1071/sh10163 ◽

2011 ◽

Vol 8 (4) ◽

pp. 512 ◽

Cited By ~ 10

Author(s):

Oluwaseun Falade-Nwulia ◽

Chloe L. Thio

Keyword(s):

Liver Disease ◽

Antiretroviral Therapy ◽

Hiv Infection ◽

Highly Active Antiretroviral Therapy ◽

Future Research ◽

Hiv Replication ◽

Highly Active ◽

Living With Hiv ◽

The Impact ◽

Hiv Negative

The life expectancy of HIV-infected patients has increased due to the efficacy of highly active antiretroviral therapy (HAART) in controlling HIV replication; thus, the population living with HIV infection is steadily aging. Liver-related morbidity and mortality has emerged as a leading problem in HIV-infected patients. Since aging, HIV infection and HAART all affect the liver, understanding the impact of the combination of these factors on liver disease is crucial for optimisation of care in the aging HIV-infected population. This review will focus on the current understanding of liver disease in older (>50 years old) HIV-negative individuals and in HIV-infected individuals. Areas for future research in the area of HIV, liver disease and aging will also be discussed.

Download Full-text

Human Immunodeficiency Virus Type-1 (HIV-1) Transcriptional Regulation, Latency and Therapy in the Central Nervous System

Vaccines ◽

10.3390/vaccines9111272 ◽

2021 ◽

Vol 9 (11) ◽

pp. 1272

Author(s):

Joseph Hokello ◽

Adhikarimayum Lakhikumar Sharma ◽

Priya Tyagi ◽

Alok Bhushan ◽

Mudit Tyagi

Keyword(s):

Central Nervous System ◽

Human Immunodeficiency Virus ◽

Nervous System ◽

Transcriptional Regulation ◽

Antiretroviral Therapy ◽

Hiv Infection ◽

Combination Antiretroviral Therapy ◽

Hiv Replication ◽

Immunodeficiency Virus ◽

The Central Nervous System

The central nervous system (CNS) is highly compartmentalized and serves as a specific site of human immunodeficiency virus (HIV) infection. Therefore, an understanding of the cellular populations that are infected by HIV or that harbor latent HIV proviruses is imperative in the attempts to address cure strategies, taking into account that HIV infection and latency in the CNS may differ considerably from those in the periphery. HIV replication in the CNS is reported to persist despite prolonged combination antiretroviral therapy due to the inability of the current antiretroviral drugs to penetrate and cross the blood–brain barrier. Consequently, as a result of sustained HIV replication in the CNS even in the face of combination antiretroviral therapy, there is a high incidence of HIV-associated neurocognitive disorders (HAND). This article, therefore, provides a comprehensive review of HIV transcriptional regulation, latency, and therapy in the CNS.

Download Full-text

HIV and AIDS

10.2310/neuro.1150 ◽

2018 ◽

Author(s):

Daniel R. Kuritzkes

Keyword(s):

Black Women ◽

Antiretroviral Therapy ◽

Hiv Infection ◽

Highly Active Antiretroviral Therapy ◽

The United States ◽

Hiv And Aids ◽

Hiv Care ◽

Hiv Replication ◽

Quarter Century ◽

Treatment And Prevention

In the quarter-century since the first report of AIDS in the United States, HIV infection has spread throughout the population, disproportionately affecting black women, Hispanic women, and men who have sex with men. The prognosis for persons infected with HIV has improved dramatically with the introduction and evolution of highly active antiretroviral therapy (HAART). The underlying principle of HAART is that a combination of potent antiretrovirals, each of which requires different mutations in the HIV genome for resistance to develop, can suppress replication sufficiently to prevent mutation and the emergence of resistance. The prospect that currently available antiretroviral therapy (ART) regimens may suppress HIV replication indefinitely provides the hope that infected patients will have life expectancies similar to those of age-matched uninfected individuals. For these patients, HIV care has shifted from an emphasis on treatment and prevention of the complications of HIV disease itself to a focus on suppression of HIV replication and management of short- and long-term complications of HIV, ART toxicities, and aging. This chapter describes the epidemiology, pathophysiology and pathogenesis, prevention, diagnosis, and management of acute and chronic HIV infection and AIDS, with figures and tables illustrating each chapter section. This review contains 9 highly rendered figures, 22 tables, and 248 references.

Download Full-text

Unique Gut Microbiome in HIV Patients on Antiretroviral Therapy (ART) Suggests Association with Chronic Inflammation

Microbiology Spectrum ◽

10.1128/spectrum.00708-21 ◽

2021 ◽

Author(s):

Aya Ishizaka ◽

Michiko Koga ◽

Taketoshi Mizutani ◽

Prince Kofi Parbie ◽

Diki Prawisuda ◽

...

Keyword(s):

Gastrointestinal Tract ◽

T Cell ◽

Antiretroviral Therapy ◽

Hiv Infection ◽

Chronic Inflammation ◽

Gut Microbiome ◽

Hiv Replication ◽

Major Site ◽

Age Related

Chronic inflammation is a hallmark of HIV infection and is associated with the development and progression of age-related comorbidities. Although the gastrointestinal tract is a major site of HIV replication and CD4 + T-cell depletion, the role of HIV-associated imbalance of gut microbiome in chronic inflammation is unclear.

Download Full-text

HIV and AIDS

10.2310/tywc.1150 ◽

2018 ◽

Author(s):

Daniel R. Kuritzkes

Keyword(s):

Black Women ◽

Antiretroviral Therapy ◽

Hiv Infection ◽

Highly Active Antiretroviral Therapy ◽

The United States ◽

Hiv And Aids ◽

Hiv Care ◽

Hiv Replication ◽

Quarter Century ◽

Treatment And Prevention

In the quarter-century since the first report of AIDS in the United States, HIV infection has spread throughout the population, disproportionately affecting black women, Hispanic women, and men who have sex with men. The prognosis for persons infected with HIV has improved dramatically with the introduction and evolution of highly active antiretroviral therapy (HAART). The underlying principle of HAART is that a combination of potent antiretrovirals, each of which requires different mutations in the HIV genome for resistance to develop, can suppress replication sufficiently to prevent mutation and the emergence of resistance. The prospect that currently available antiretroviral therapy (ART) regimens may suppress HIV replication indefinitely provides the hope that infected patients will have life expectancies similar to those of age-matched uninfected individuals. For these patients, HIV care has shifted from an emphasis on treatment and prevention of the complications of HIV disease itself to a focus on suppression of HIV replication and management of short- and long-term complications of HIV, ART toxicities, and aging. This chapter describes the epidemiology, pathophysiology and pathogenesis, prevention, diagnosis, and management of acute and chronic HIV infection and AIDS, with figures and tables illustrating each chapter section. This review contains 9 highly rendered figures, 22 tables, and 248 references.

Download Full-text