scholarly journals The Continuing Evolution of HIV-1 Therapy: Identification and Development of Novel Antiretroviral Agents Targeting Viral and Cellular Targets

2012 ◽  
Vol 2012 ◽  
pp. 1-17 ◽  
Author(s):  
Tracy L. Hartman ◽  
Robert W. Buckheit
Keyword(s):  
Cellular Targets ◽  
Treatment Regimens ◽  
Highly Active ◽  
Antiretroviral Therapies ◽  
Pediatric Populations ◽  
Developed World ◽  
Anti Hiv ◽  
Virus Isolates ◽  
Hiv 1 ◽  
Drug Resistant Virus

During the past three decades, over thirty-five anti-HIV-1 therapies have been developed for use in humans and the progression from monotherapeutic treatment regimens to today’s highly active combination antiretroviral therapies has had a dramatic impact on disease progression in HIV-1-infected individuals. In spite of the success of AIDS therapies and the existence of inhibitors of HIV-1 reverse transcriptase, protease, entry and fusion, and integrase, HIV-1 therapies still have a variety of problems which require continued development efforts to improve efficacy and reduce toxicity, while making drugs that can be used throughout both the developed and developing world, in pediatric populations, and in pregnant women. Highly active antiretroviral therapies (HAARTs) have significantly delayed the progression to AIDS, and in the developed world HIV-1-infected individuals might be expected to live normal life spans while on lifelong therapies. However, the difficult treatment regimens, the presence of class-specific drug toxicities, and the emergence of drug-resistant virus isolates highlight the fact that improvements in our therapeutic regimens and the identification of new and novel viral and cellular targets for therapy are still necessary. Antiretroviral therapeutic strategies and targets continue to be explored, and the development of increasingly potent molecules within existing classes of drugs and the development of novel strategies are ongoing.

Highly active antiretroviral therapies among HIV-1-infected children in Abidjan, Côte d'Ivoire

AIDS ◽  
2004 ◽  
Vol 18 (14) ◽  
pp. 1905-1913 ◽  
Author(s):  
Patricia Fassinou ◽  
Narcisse Elenga ◽  
François Rouet ◽  
Rockiath Laguide ◽  
Kouakou A Kouakoussui ◽  
...  
Keyword(s):  
Cote D'ivoire ◽  
Côte D’Ivoire ◽  
Cote D’Ivoire ◽  
Highly Active ◽  
Antiretroviral Therapies ◽  
Côte D'ivoire ◽  
Hiv 1

A therapeutic HIV-1 vaccine enhances anti-HIV-1 immune responses in patients under highly active antiretroviral therapy

Vaccine ◽  
2016 ◽  
Vol 34 (19) ◽  
pp. 2225-2232 ◽  
Author(s):  
Frank Y. Tung ◽  
Jack K. Tung ◽  
Suresh Pallikkuth ◽  
Savita Pahwa ◽  
Margaret A. Fischl
Keyword(s):  
Antiretroviral Therapy ◽  
Immune Responses ◽  
Highly Active Antiretroviral Therapy ◽  
Highly Active ◽  
Anti Hiv ◽  
Hiv 1

scholarly journals Insights into the HIV Latency and the Role of Cytokines

Pathogens ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 137 ◽  
Author(s):  
Joseph Hokello ◽  
Adhikarimayum Lakhikumar Sharma ◽  
Manjari Dimri ◽  
Mudit Tyagi
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Immunological Response ◽  
Hiv Latency ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Treatment Regimens ◽  
Highly Active ◽  
Latent Hiv ◽  
Hiv 1

Human immunodeficiency virus-1 (HIV-1) has the ability to infect latently at the level of individual CD4+ cells. Latent HIV-1 proviruses are transcriptionally silent and immunologically inert, but are still capable of reactivating productive lytic infection following cellular activation. These latent viruses are the main obstacle in the eradication of HIV-1, because current HIV-1 treatment regimens are ineffective against them. Normal immunological response against an antigen activates CD4+ naïve T cells. The activated CD4+ naïve T cells undergo cell cycle, resulting in further transformation and profound proliferation to form effector CD4+ T-cells. Notably, in HIV-1 infected individuals, some of the effector CD4+ T cells get infected with HIV-1. Upon fulfillment of their effector functions, almost all activated CD4+ T cells are committed to apoptosis or programmed cell death, but a miniscule fraction revert to quiescence and become resting memory CD4+ T cells to mediate a rapid immunological response against the same antigen in the future. However, due to the quiescent nature of the resting memory T cells, the integrated HIV-1 becomes transcriptionally silent and acquires a latent phenotype. Following re-exposure to the same antigen, memory cells and integrated HIV-1 are stimulated. The reactivated latent HIV provirus subsequently proceeds through its life cycle and eventually leads to the production of new viral progeny. Recently, many strategies against HIV-1 latency have been developed and some of them have even matured to the clinical level, but none can yet effectively eliminate the latent HIV reservoir, which remains a barrier to HIV-1 cure. Therefore, alternative strategies to eradicate latent HIV need to be considered. This review provides vital knowledge on HIV latency and on strategies to supplement highly active anti-retroviral therapy (HAART) with cytokine-mediated therapeutics for dislodging the latent HIV reservoirs in order to open up new avenues for curing HIV.

scholarly journals Impact of highly active antiretroviral therapy on the maturation of anti-HIV-1 antibodies during primary HIV-1 infection

HIV Medicine ◽  
2006 ◽  
Vol 7 (8) ◽  
pp. 514-519 ◽  
Author(s):  
L Adalid-Peralta ◽  
L Grangeot-Keros ◽  
A Rudent ◽  
N Ngo-Giang-Huong ◽  
R Krzysiek ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Highly Active Antiretroviral Therapy ◽  
Highly Active ◽  
Anti Hiv ◽  
Hiv 1

scholarly journals The Interplay of HIV-1 and Macrophages in Viral Persistence

2021 ◽  
Vol 12 ◽  
Author(s):  
Chynna M. Hendricks ◽  
Thaissa Cordeiro ◽  
Ana Paula Gomes ◽  
Mario Stevenson
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Viral Persistence ◽  
Vital Role ◽  
Highly Active ◽  
Antiretroviral Therapies ◽  
Memory Cd4 T Cells ◽  
Hiv 1

HIV-1 has evolved mechanisms to evade host cell immune responses and persist for lifelong infection. Latent cellular reservoirs are responsible for this persistence of HIV-1 despite the powerful effects of highly active antiretroviral therapies (HAART) to control circulating viral load. While cellular reservoirs have been extensively studied, much of these studies have focused on peripheral blood and resting memory CD4+ T cells containing latent HIV-1 provirus; however, efforts to eradicate cellular reservoirs have been stunted by reservoirs found in tissues compartments that are not easily accessible. These tissues contain resting memory CD4+ T cells and tissue resident macrophages, another latent cellular reservoir to HIV-1. Tissue resident macrophages have been associated with HIV-1 infection since the 1980s, and evidence has continued to grow regarding their role in HIV-1 persistence. Specific biological characteristics play a vital role as to why macrophages are latent cellular reservoirs for HIV-1, and in vitro and in vivo studies exhibit how macrophages contribute to viral persistence in individuals and animals on antiretroviral therapies. In this review, we characterize the role and evolutionary advantages of macrophage reservoirs to HIV-1 and their contribution to HIV-1 persistence. In acknowledging the interplay of HIV-1 and macrophages in the host, we identify reasons why current strategies are incapable of eliminating HIV-1 reservoirs and why efforts must focus on eradicating reservoirs to find a future functional cure.

scholarly journals Highly Active Antiretroviral Therapies Are Effective against HIV-1 Cell-to-Cell Transmission

2014 ◽  
Vol 10 (2) ◽  
pp. e1003982 ◽  
Author(s):  
Luis M. Agosto ◽  
Peng Zhong ◽  
James Munro ◽  
Walther Mothes
Keyword(s):  
Highly Active ◽  
Antiretroviral Therapies ◽  
Cell Transmission ◽  
Hiv 1

scholarly journals Exploiting the Anti-HIV-1 Activity of Acyclovir: Suppression of Primary and Drug-Resistant HIV Isolates and Potentiation of the Activity by Ribavirin

2012 ◽  
Vol 56 (5) ◽  
pp. 2604-2611 ◽  
Author(s):  
Christophe Vanpouille ◽  
Andrea Lisco ◽  
Andrea Introini ◽  
Jean-Charles Grivel ◽  
Arshi Munawwar ◽  
...  
Keyword(s):  
Highly Active Antiretroviral Therapy ◽  
Ex Vivo ◽  
Suppressive Therapy ◽  
Highly Active ◽  
Clinical Investigations ◽  
Simplex Virus ◽  
Herpes Simplex Virus 2 ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Viral Isolates

ABSTRACTMultiple clinical trials have demonstrated that herpes simplex virus 2 (HSV-2) suppressive therapy using acyclovir (ACV) or valacyclovir in HIV-1/HSV-2-infected persons increased the patient's survival and decreased the HIV-1 load. It has been shown that the incorporation of ACV-monophosphate into the nascent DNA chain instead of dGMP results in the termination of viral DNA elongation and directly inhibits laboratory strains of HIV-1. We evaluated here the anti-HIV activity of ACV against primary HIV-1 isolates of different clades and coreceptor specificity and against viral isolates resistant to currently used drugs, including zidovudine, lamivudine, nevirapine, a combination of nucleoside reverse transcriptase inhibitors (NRTIs), a fusion inhibitor, and two protease inhibitors. We found that, at clinically relevant concentrations, ACV inhibits the replication of these isolates in human tissues infectedex vivo. Moreover, addition of ribavirin, an antiviral capable of depleting the pool of intracellular dGTP, potentiated the ACV-mediated HIV-1 suppression. These data warrant further clinical investigations of the benefits of using inexpensive and safe ACV alone or in combination with other drugs against HIV-1, especially to complement or delay highly active antiretroviral therapy (HAART) initiation in low-resource settings.

scholarly journals A Novel Tricyclic Ligand-Containing Nonpeptidic HIV-1 Protease Inhibitor, GRL-0739, Effectively Inhibits the Replication of Multidrug-Resistant HIV-1 Variants and Has a Desirable Central Nervous System Penetration PropertyIn Vitro

2015 ◽  
Vol 59 (5) ◽  
pp. 2625-2635 ◽  
Author(s):  
Masayuki Amano ◽  
Yasushi Tojo ◽  
Pedro Miguel Salcedo-Gómez ◽  
Garth L. Parham ◽  
Prasanth R. Nyalapatla ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Protease Inhibitor ◽  
Serum Proteins ◽  
Multidrug Resistant ◽  
Highly Active ◽  
Cns Penetration ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACTWe report here that GRL-0739, a novel nonpeptidic HIV-1 protease inhibitor containing a tricycle (cyclohexyl-bis-tetrahydrofuranylurethane [THF]) and a sulfonamide isostere, is highly active against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC50], 0.0019 to 0.0036 μM), with minimal cytotoxicity (50% cytotoxic concentration [CC50], 21.0 μM). GRL-0739 blocked the infectivity and replication of HIV-1NL4-3variants selected by concentrations of up to 5 μM ritonavir or atazanavir (EC50, 0.035 to 0.058 μM). GRL-0739 was also highly active against multidrug-resistant clinical HIV-1 variants isolated from patients who no longer responded to existing antiviral regimens after long-term antiretroviral therapy, as well as against the HIV-2RODvariant. The development of resistance against GRL-0739 was substantially delayed compared to that of amprenavir (APV). The effects of the nonspecific binding of human serum proteins on the anti-HIV-1 activity of GRL-0739 were insignificant. In addition, GRL-0739 showed a desirable central nervous system (CNS) penetration property, as assessed using a novelin vitroblood-brain barrier model. Molecular modeling demonstrated that the tricyclic ring and methoxybenzene of GRL-0739 have a larger surface and make greater van der Waals contacts with protease than in the case of darunavir. The present data demonstrate that GRL-0739 has desirable features as a compound with good CNS-penetrating capability for treating patients infected with wild-type and/or multidrug-resistant HIV-1 variants and that the newly generated cyclohexyl-bis-THF moiety with methoxybenzene confers highly desirable anti-HIV-1 potency in the design of novel protease inhibitors with greater CNS penetration profiles.

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