Antiviral Activity of Lamivudine in Salvage Therapy for Multidrug‐Resistant HIV‐1 Infection

Campbell, Thomas; Shulman, Nancy S.; Johnson, Steven C.; Zolopa, Andrew; Young, Russell; Bushman, Lane R.; Fletcher, Courtney V.; Lanier, E. Randall; Merigan, Thomas C.; Kuritzkes, Daniel R.

doi:10.1086/430709

Cited by 108 publications

(70 citation statements)

References 20 publications

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“…However, the loss of M184V occurred well after the rise in viral load, suggesting that the residual antiviral activity of nucleosides, rather than an increase in viral fitness, was the cause of the viral rebound (38). Similar observations were made in nonrandomized studies of lamivudine or lamivudine-zidovudine interruption (28,59). Selective interruption of the fusion inhibitor enfuvirtide leads to prompt but limited increases in viral load (ϳ0.1 to 0.2 log 10 copies/ml), indicating that this drug also has some limited efficacy despite the presence of drug-resistant variants (39).…”

Section: Outcomes In Chronic Hiv-1 Infectionsupporting

confidence: 54%

“…However, other studies have shown that lamivudine does exert some antiretroviral effect on the M184V mutant, suggesting that the incomplete viral rebounds that occur may represent residual antiviral activity rather than selection for a mutant with reduced fitness (139). Studies of selective lamivudine treatment interruptions demonstrate increases in viral load before reversion of the M184V mutant, also supporting the hypothesis that lamivudine retains antiretroviral activity against M184V (28).…”

Section: Mutations Conferring Resistance To Reversementioning

confidence: 75%

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Clinical Significance of Human Immunodeficiency Virus Type 1 Replication Fitness

Dykes

Demeter

2007

Clin Microbiol Rev

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SUMMARY The relative fitness of a variant, according to population genetics theory, is that variant's relative contribution to successive generations. Most drug-resistant human immunodeficiency virus type 1 (HIV-1) variants have reduced replication fitness, but at least some of these deficits can be compensated for by the accumulation of second-site mutations. HIV-1 replication fitness also appears to influence the likelihood of a drug-resistant mutant emerging during treatment failure and is postulated to influence clinical outcomes. A variety of assays are available to measure HIV-1 replication fitness in cell culture; however, there is no agreement regarding which assays best correlate with clinical outcomes. A major limitation is that there is no high-throughput assay that incorporates an internal reference strain as a control and utilizes intact virus isolates. Some retrospective studies have demonstrated statistically significant correlations between HIV-1 replication fitness and clinical outcomes in some patient populations. However, different studies disagree as to which clinical outcomes are most closely associated with fitness. This may be in part due to assay design, sample size limitations, and differences in patient populations. In addition, the strength of the correlations between fitness and clinical outcomes is modest, suggesting that, at present, it would be difficult to utilize these assays for clinical management.

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Section: Outcomes In Chronic Hiv-1 Infectionsupporting

confidence: 54%

Section: Mutations Conferring Resistance To Reversementioning

confidence: 75%

Clinical Significance of Human Immunodeficiency Virus Type 1 Replication Fitness

Dykes

Demeter

2007

Clin Microbiol Rev

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“…HIV-1 mutants with diminished replication fitness have been known to provide clinical benefit in practice. For example, many clinicians have chosen to continue to use 3TC even after the 3TC resistance mutation M184V has emerged to take advantage of the viral replicative defect caused by this mutation (18).…”

Section: Discussionmentioning

confidence: 99%

Protective HLA Class I Alleles That Restrict Acute-Phase CD8 ⁺ T-Cell Responses Are Associated with Viral Escape Mutations Located in Highly Conserved Regions of Human Immunodeficiency Virus Type 1

Wang

Carlson

et al. 2009

J Virol

105

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The control of human immunodeficiency virus type 1 (HIV-1) associated with particular HLA class I alleles suggests that some CD8؉ T-cell responses may be more effective than others at containing HIV-1. Unfortunately, substantial diversities in the breadth, magnitude, and function of these responses have impaired our ability to identify responses most critical to this control. It has been proposed that CD8 responses targeting conserved regions of the virus may be particularly effective, since the development of cytotoxic T-lymphocyte (CTL) escape mutations in these regions may significantly impair viral replication. To address this hypothesis at the population level, we derived near-full-length viral genomes from 98 chronically infected individuals and identified a total of 76 HLA class I-associated mutations across the genome, reflective of CD8 responses capable of selecting for sequence evolution. The majority of HLA-associated mutations were found in p24 Gag, Pol, and Nef. Reversion of HLA-associated mutations in the absence of the selecting HLA allele was also commonly observed, suggesting an impact of most CTL escape mutations on viral replication. Although no correlations were observed between the number or location of HLA-associated mutations and protective HLA alleles, limiting the analysis to mutations selected by acute-phase immunodominant responses revealed a strong positive correlation between mutations at conserved residues and protective HLA alleles. These data suggest that control of HIV-1 may be associated with acute-phase CD8 responses capable of selecting for viral escape mutations in highly conserved regions of the virus, supporting the inclusion of these regions in the design of an effective vaccine.

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“…In addition, individuals with documented drug resistance have lower levels of CD4 ϩ and CD8 ϩ T cell activation, experience lower rates of CD4 ϩ depletion, and progress more slowly to AIDS than do untreated HIV-infected individuals, independently of plasma HIV RNA levels (28)(29)(30)(31)(32). The reduced ability of drug-resistant viruses to contribute to disease progression may result from particular drug resistance mutations that impede viral replicative capacity, thus decreasing the activation of bystander T cells (29,33). Conversely, the presence of CXCR4-tropic viruses was associated with higher levels of inflammatory markers in one study (34) but with no difference in levels of inflammatory markers in another (35).…”

mentioning

confidence: 99%

Association between Latent Proviral Characteristics and Immune Activation in Antiretrovirus-Treated Human Immunodeficiency Virus Type 1-Infected Adults

Liang

Sceats

Bayless

et al. 2014

J Virol

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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. IMPORTANCEChronic 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.

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Antiviral Activity of Lamivudine in Salvage Therapy for Multidrug‐Resistant HIV‐1 Infection

Abstract: In select cases of multidrug-resistant HIV-1 infection, lamivudine contributes to suppression of HIV-1 replication, despite the presence of M184V mutations and lamivudine resistance.

Cited by 108 publications

References 20 publications

Clinical Significance of Human Immunodeficiency Virus Type 1 Replication Fitness

Clinical Significance of Human Immunodeficiency Virus Type 1 Replication Fitness

Protective HLA Class I Alleles That Restrict Acute-Phase CD8 ⁺ T-Cell Responses Are Associated with Viral Escape Mutations Located in Highly Conserved Regions of Human Immunodeficiency Virus Type 1

Association between Latent Proviral Characteristics and Immune Activation in Antiretrovirus-Treated Human Immunodeficiency Virus Type 1-Infected Adults

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Antiviral Activity of Lamivudine in Salvage Therapy for Multidrug‐Resistant HIV‐1 Infection

Abstract: In select cases of multidrug-resistant HIV-1 infection, lamivudine contributes to suppression of HIV-1 replication, despite the presence of M184V mutations and lamivudine resistance.

Cited by 108 publications

References 20 publications

Clinical Significance of Human Immunodeficiency Virus Type 1 Replication Fitness

Clinical Significance of Human Immunodeficiency Virus Type 1 Replication Fitness

Protective HLA Class I Alleles That Restrict Acute-Phase CD8 + T-Cell Responses Are Associated with Viral Escape Mutations Located in Highly Conserved Regions of Human Immunodeficiency Virus Type 1

Association between Latent Proviral Characteristics and Immune Activation in Antiretrovirus-Treated Human Immunodeficiency Virus Type 1-Infected Adults

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Protective HLA Class I Alleles That Restrict Acute-Phase CD8 ⁺ T-Cell Responses Are Associated with Viral Escape Mutations Located in Highly Conserved Regions of Human Immunodeficiency Virus Type 1