HIV-1 Functional Cure: Will the Dream Come True?

The reservoir of human immunodeficiency virus type 1 (HIV-1), a long-lived pool of latently infected cells harboring replication-competent viruses, is the major obstacle to curing acquired immune deficiency syndrome (AIDS). Although the combination antiretroviral therapy (cART) can successfully suppress HIV-1 viremia and significantly delay the progression of the disease, it cannot eliminate the viral reservoir and the patient must continue to take anti-viral medicines for life. 

Currently, the appearance of the ‘Berlin patient’, the ‘Boston patients’, and the ‘Mississippi baby’ have inspired many therapeutic strategies for HIV-1 aimed at curing efforts. However, the specific eradication of viral latency and the recovery and optimization of the HIV-1-specific immune surveillance are major challenges to achieving such a cure. Here, we summarize recent studies addressing the mechanisms underlying the viral latency and define two categories of viral reservoir: ‘shallow’ and ‘deep’. We also present the current strategies and recent advances in the development of a functional cure for HIV-1, focusing on full/partial replacement of the immune system, ‘shock and kill’, and ‘permanent silencing’ approaches.

Below:  A feasible strategy for the functional cure of HIV-1. Firstly, ‘shock and kill’ strategies could be quite useful in kicking out the ‘shallow’ latent viruses and eliminating them. Then, ‘silencing’ strategies, which permanently inactivate the ‘deeply’ silenced viruses, accompanied by potent anti-HIV-1 immune surveillance, could subsequently be utilized to achieve the functional cure of HIV-1

Below:  Strategies for recovery and optimization of anti-HIV-1 immune surveillance. The combination of bNAbs with autologous adoptive transfer of HIV-1-specific CD8 + T cells and/or HIV-1-resistant CD4 + T cells could be an effective therapeutic modality for the functional cure of HIV-1

Full article at:  http://goo.gl/eRNiKQ

By: Chao Liu¹², Xiancai Ma¹², Bingfeng Liu¹², Cancan Chen¹² and Hui Zhang^12*

¹Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China

²Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China

 

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Intensifying Antiretroviral Therapy With Raltegravir and Maraviroc During Early Human Immunodeficiency Virus (HIV) Infection Does Not Accelerate HIV Reservoir Reduction

Persistent human immunodeficiency virus (HIV) within the CD4⁺ T-cell reservoir is an obstacle to eradication. We hypothesized that adding raltegravir and maraviroc to standard combination antiretroviral therapy (cART) during early HIV infection could substantially reduce viral reservoirs as a step towards eradication.

A prospective, randomized, double-blinded, placebo-controlled pilot trial enrolled 32 participants with documented early (<6 months) HIV infection to either standard cART (emtricitabine/tenofovir/lopinavir/ritonavir) or intensive cART (standard regimen + raltegravir/maraviroc). Human immunodeficiency virus reservoirs were assessed at baseline and at 48 weeks by (1) proviral DNA, (2) cell-associated RNA, and (3) replication-competent virus, all from purified blood CD4⁺ T cells, and (4) gut proviral DNA. A multiassay algorithm (MAA) on baseline sera estimated timing of infection.

Thirty individuals completed the study to the 48-week endpoint. The reduction in blood proviral burden was −1.03 log DNA copies/10⁶ CD4⁺ T cells versus −.84 log in the standard and intensive groups, respectively (P = .056). Overall, there was no significant difference in the rate of decline of HIV-associated RNA, replication-competent virus in blood CD4⁺ T cells, nor proviral gut HIV DNA to 48 weeks. Individuals who presented with more recent HIV infection had significantly lower virus reservoirs, and cART tended to reduce their reservoirs to a greater extent.

Intensive cART led to no additional reduction in the blood virus reservoir at 48 weeks compared with standard cART. Human immunodeficiency virus reservoir size is smaller earlier in HIV infection. Other novel treatment strategies in combination with early cART will be needed to eliminate the HIV latent reservoir.

Below:  Effect of treatments on plasma viral load and peripheral CD4/CD8 counts. Plasma virus load kinetics on treatment for 30 subjects completing primary endpoint shown in (A) and CD4 and CD8 counts at baseline and 48 weeks in (B). Medians are depicted.

Below:  Human immunodeficiency virus (HIV) viral reservoir determinations for standard and intensive therapy groups. In (A) are kinetics of proviral DNA copies/million isolated CD4+ T cells from peripheral blood mononuclear cells (PBMC) (n = 30, medians with interquartile ranges); in (B) are baseline 24- and 48-week HIV RNA/µg of RNA from isolated CD4+ T cells from PBMC (n = 30, medians with interquartile ranges); in (C) are infectious HIV units cultured/million isolated CD4+ T cells from PBMC (n = 29 evaluable), with summary graph far right (medians with interquartile ranges); and in (D) are proviral DNA copies/million isolated CD8-depleted cells from sigmoid colon mononuclear cells (n = 19 evaluable), with summary graph far right (medians with interquartile ranges). Abbreviation: VL, viral load.

Full article at: http://goo.gl/dmuX9X

By: Mario Ostrowski,1,2,4 Erika Benko,3 Feng Yun Yue,2 Connie J. Kim,2 Sanja Huibner,2 Terry Lee,7,8 Joel Singer,7,8 Jim Pankovich,7,8 Oliver Laeyendecker,5,6 Rupert Kaul,1,2 Gabor Kandel,2,4 and Colin Kovacs2,3

¹Departments of Immunology

²Medicine, University of Toronto

³Maple Leaf Clinic

⁴Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada

⁵Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda

⁶Johns Hopkins University, Baltimore, Maryland

⁷University of British Columbia

⁸CIHR Canadian HIV Trials Network, Vancouver, British Columbia, Canada

Correspondence: Mario Ostrowski, MD, Room 6271, Medical Sciences Building, 1 King's College Circle, Toronto, ON M5S1A8, Canada (Email:moc.liamg@ikswortso.oiram).

   

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HIV Persistence in the Setting of Antiretroviral Therapy: When, Where and How Does HIV Hide?

Advances in the treatment of HIV infection have dramatically reduced the death rate from AIDS and improved the quality of life of many HIV-infected individuals. However, the possible long-term toxicity associated with antiretroviral therapy (ART), stigma and cost, all contribute to the necessity of finding a cure for HIV infection. In infected individuals taking ART, HIV persists in a small number of cells that can survive for the lifetime of the infected person. These persistently infected cells, usually referred as the ‘reservoirs for HIV infection’, are the main barriers to a cure. The diversity of the tissues and cellular types in which HIV persists, as well as the multiplicity of the molecular mechanisms contributing to HIV persistence, complicate the efforts to develop a safe, effective, and globally accessible cure for HIV. In this review, we summarise recent data that contribute to our understanding of HIV persistence during ART by addressing three questions pertaining to the HIV reservoir: (1) when is the reservoir established; (2) where is the reservoir maintained; and (3) how does the reservoir persist?

Below:  Clinical definition of the HIV reservoir. Untreated HIV infection is characterised by high levels of viral replication that can be measured in the plasma of HIV-infected individuals. ART reduces viral replication to undetectable levels by standard viral load measurements. When ART is interrupted, HIV replication resumes, revealing that HIV persisted in cellular and anatomical ‘reservoirs’ during ART and that these reservoirs can re-ignite infection.

Full article at: http://goo.gl/RgZMc6

By: Deanna A. Kulpa1 and Nicolas Chomont2,*

1Vaccine and Gene Therapy Institute Florida, Port St Lucie, Florida, USA

2Department of Microbiology, Infectiology and Immunology, Université de Montréal, Faculty of Medicine, and Centre de Recherche du CHUM, Montréal, Quebec, Canada

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