Acute HIV revisited: new opportunities for treatment and prevention

Pilcher, Christopher D.; Eron, Joseph J.; Galvin, Shannon; Cohen, Myron S.

doi:10.1172/jci21540

Cited by 128 publications

(67 citation statements)

References 95 publications

(29 reference statements)

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“…[21][22][23] Here we show that HIV-1 could also induce disruption of tight junction structures in HRPE cells. Notably, we used HIV-1 in the in vitro experiments at a high level resembling the high viral load in the HIV-1-infected patients in the acute phase of infection or in AIDS stage, 42 reflecting the facts that viruses might cause this ocular pathological abnormality at either early phase of infection or the late stage of infection. Disruption of barrier function of HRPE monolayer is mediated by HIV-1 gp120 (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

HIV-1 impairs human retinal pigment epithelial barrier function: possible association with the pathogenesis of HIV-associated retinopathy

Tan

Duan

Xun

et al. 2014

Laboratory Investigation

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The breakdown of human retinal pigment epithelial (HRPE) barrier is considered as the etiology of retinopathy, which affects the quality of life of HIV/AIDS patients. Here we demonstrate that HIV-1 could directly impair HRPE barrier function, which leads to the translocation of HIV-1 and bacteria. HRPE cells (D407) were grown to form polarized, confluent monolayers and treated with different HIV-1 infectious clones. A significant increase of monolayer permeability, as measured by trans-epithelial electrical resistance (TEER) and apical-basolateral movements of sodium fluorescein, was observed. Disrupted tightness of HRPE barrier was associated with the downregulation of several tight junction proteins in D407 cells, including ZO-1, Occludin, Claudin-1, Claudin-2, Claudin-3, Claudin-4, and Claudin-5, after exposure to HIV-1, without affecting the viability of cells. HIV-1 gp120 was shown to participate in the alteration of barrier properties, as evidenced by decreased TEER and weakened expression of tight junction proteins in D407 monolayers after exposure to pseudotyped HIV-1, UV-inactivated HIV-1, and free gp120, but not to an envelope (Env)-defective mutant of HIV. Furthermore, exposure to HIV-1 particles could induce the release of pro-inflammatory cytokines in D407, including IL-6 and MCP-1, both of which downregulated the expression of ZO-1 in the HRPE barrier. Disrupted HRPE monolayer allowed translocation of HIV-1 and bacteria across the epithelium. Overall, these findings suggest that HIV-1 may exploit its Env glycoprotein to induce an inflammatory state in HRPE cells, which could result in impairment of HRPE monolayer integrity, allowing virus and bacteria existing in ocular fluids to cross the epithelium and penetrate the HRPE barrier. Our study highlights the role of HIV-1 in the pathogenesis of HIV/AIDS-related retinopathy and suggests potential therapeutic targets for this ocular complication.

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Section: Discussionmentioning

confidence: 99%

HIV-1 impairs human retinal pigment epithelial barrier function: possible association with the pathogenesis of HIV-associated retinopathy

Tan

Duan

Xun

et al. 2014

Laboratory Investigation

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Section: Introductionmentioning

confidence: 99%

“…[6]. The natural history of untreated infection then involves years of clinical stability, followed by inexorable CD4+ Tcell count decline (reviewed in [7]). In the advanced immunosuppression setting, antiretroviral therapy (ART) results in rapid plasma viremia decline, CD4+ T-cell count improvement, and decreased disease progression and mortality [8].…”

mentioning

confidence: 99%

“…In the advanced immunosuppression setting, antiretroviral therapy (ART) results in rapid plasma viremia decline, CD4+ T-cell count improvement, and decreased disease progression and mortality [8]. Treatment during acute seroconversion also hastens the viremia decline beyond the natural equilibration seen in untreated patients [9,10], but there is no consensus regarding the long-term risks and benefits of early treatment [7,8,11].Very limited data directly compare treatment responses among individuals with early and late stage disease. It remains unclear whether comparably high viremia levels observed at the opposite ends of the disease spectrum would decline at the same rate in response to identical treatment interventions.…”

mentioning

confidence: 99%

“…Here we found no significant difference in first phase clearance between groups, although there was a trend in advanced patients for higher mean protease inhibitor levels to correlate with more rapid virologic suppression [for indinavir (r = 0.82) and nelfinavir (r = 0.42) but not the nelfinavir metabolite (r = −0.24)]. Overall, patients with cases of undetectable levels of either protease inhibitor had longer mean time to treatment response (19.6 weeks) [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] compared with patients with always-detectable levels (15.6 weeks) [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]. …”

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confidence: 99%

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Treatment response in acute/early infection versus advanced AIDS: equivalent first and second phases of HIV RNA decline

Kilby¹,

Lee

Hazelwood³

et al. 2008

Aids

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Objective-Compare the initial phases of virologic decay when acute/early and advanced HIVinfected adults are administered the same treatment regimen.Design-Mathematical modeling of a previously completed prospective treatment pilot study involving treatment-naive patients with early and advanced immunosuppression.Methods-We analyzed data from a treatment protocol in which 18 individuals with acute or recent HIV-1 seroconversion and six patients with advanced AIDS were administered the same four-drug antiretroviral regimen. Initial treatment responses were compared by fitting a mathematical model to frequent viral load measurements in order to calculate the first and second phase kinetics of viral clearance, and also by comparing viral load suppression over 24 weeks. Patients were also comprehensively compared in terms of protease inhibitor drug levels, HIVspecific immune responses at baseline, and the presence of drug resistance-conferring mutations.Results-There was no statistically meaningful difference in first phase clearance of comparable high-level viremia in the two groups, whether protease inhibitor levels were inserted into the model or 100% antiviral drug effectiveness was assumed. In contrast, acute/early patients had inferior sustained responses than advanced patients, reflecting erratic adherence.Conclusions-Despite many years of intervening immune destruction, the initial virologic decay on therapy appears to be the same at the extremes of the HIV disease spectrum. [6]. The natural history of untreated infection then involves years of clinical stability, followed by inexorable CD4+ Tcell count decline (reviewed in [7]). In the advanced immunosuppression setting, antiretroviral therapy (ART) results in rapid plasma viremia decline, CD4+ T-cell count improvement, and decreased disease progression and mortality [8]. Treatment during acute seroconversion also hastens the viremia decline beyond the natural equilibration seen in untreated patients [9,10], but there is no consensus regarding the long-term risks and benefits of early treatment [7,8,11].Very limited data directly compare treatment responses among individuals with early and late stage disease. It remains unclear whether comparably high viremia levels observed at the opposite ends of the disease spectrum would decline at the same rate in response to identical treatment interventions. Previously, we completed a pathogenesis-driven study involving both acute/early and highly advanced HIV-infected patients [12]. We revisited this unique dataset to compare and contrast treatment responses at the disease spectrum extremes. We hypothesized that virologic suppression would be more rapid and complete during acute than advanced disease, perhaps because of rescue of immune clearance mechanisms [13] or incomplete population of viral reservoirs [14]. MethodsAll studies were approved by the Institutional Review Board. Eligibility required no prior ART, Karnofsky performance of at least 80, and safety laboratory results were within acceptable rang...

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Virological characterization of patients treated early is able to control HIV‐1 replication after multiple cycles of structured therapy interruption

Rozera

Abbate

D’Offizi³

et al. 2007

Journal of Medical Virology

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This study aimed to define clinical and virological parameters associated with spontaneous control of HIV replication in patients having initiated HAART during primary HIV infection, who underwent structured therapy interruption by two protocols with either fixed or HIV viremia-guided scheme. At the end of the protocol all patients were changed to viremia-guided scheme and observed for 12 months (follow-up). Patients maintaining HIV viremia below the indications for resumption of HAART during the follow-up, were defined controllers, those who had to resume HAART were defined non-controllers. The following parameters were examined: pre-interruption therapy duration, CD4(+), HIV RNA, proviral DNA, evolution of viral quasispecies. No specific advantage was conferred by either interruption of structured therapy in the proportion of controllers and non-controllers. Pre-HAART and zenith CD4(+), pre-therapy interruption, HAART duration, but not pre-HAART HIV RNA, were significantly higher in controllers as compared to non-controllers. HIV RNA levels after the first interruption cycle of therapy were significantly lower in controllers than in non-controllers. Proviral DNA levels were also lower in controllers at this time point. HIV RNA and proviral DNA levels associated with the last interruption of therapy cycle were not different from those associated with the first cycle, and, in spite of multiple waves of virus rebound, very few gag quasispecies variants emerged in each patient. The data suggest that pre-treatment clinical parameters and virological events associated with the first viral rebound are crucial factors in determining the ability to control viral replication after multiple cycles of interruption of treatment.

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Acute HIV revisited: new opportunities for treatment and prevention

Cited by 128 publications

References 95 publications

HIV-1 impairs human retinal pigment epithelial barrier function: possible association with the pathogenesis of HIV-associated retinopathy

HIV-1 impairs human retinal pigment epithelial barrier function: possible association with the pathogenesis of HIV-associated retinopathy

Treatment response in acute/early infection versus advanced AIDS: equivalent first and second phases of HIV RNA decline

Virological characterization of patients treated early is able to control HIV‐1 replication after multiple cycles of structured therapy interruption

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