Human immunodeficiency virus type 1 pol gene mutations in an AIDS patient treated with multiple antiretroviral drugs.

ABSTRACT The T69D mutation in the human immunodeficiency virus type 1 reverse transcriptase (RT) gene has been associated with reduced susceptibility to dideoxycytosine (ddC); however, several other mutations at codon 69 have been observed in antiretroviral drug-treated patients. The Stanford HIV RT and Protease Sequence Database was interrogated and showed that 23% of patients treated with nucleoside RT inhibitors (NRTI) had mutations at codon 69. These variants included T69N, -S, -A, -G, -E, -I, and -K mutations that were present in patients treated with NRTI but not in drug-naive patients. Treatment history information showed that a substantial percentage of these codon 69 changes occurred in patients administered non-ddC-containing regimens. Different and specific patterns of other RT gene mutations were associated with the various codon 69 mutations. Drug susceptibility assays showed that viral constructs containing codon 69 variants could have reduced susceptibility to ddC and other RT inhibitors. These results suggest that the T69D mutation is not the only codon 69 variant associated with drug resistance and that ddC is not the only drug affected.

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Human immunodeficiency virus type 1 pol gene mutations which cause decreased susceptibility to 2',3'-dideoxycytidine.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.36.1.153 ◽

1992 ◽

Vol 36 (1) ◽

pp. 153-157 ◽

Cited By ~ 100

Author(s):

J E Fitzgibbon ◽

R M Howell ◽

C A Haberzettl ◽

S J Sperber ◽

D J Gocke ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Gene Mutations ◽

Immunodeficiency Virus

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Theoretical Design of a Gene Therapy To Prevent AIDS but Not Human Immunodeficiency Virus Type 1 Infection

Journal of Virology ◽

10.1128/jvi.77.18.10028-10036.2003 ◽

2003 ◽

Vol 77 (18) ◽

pp. 10028-10036 ◽

Cited By ~ 49

Author(s):

Leor S. Weinberger ◽

David V. Schaffer ◽

Adam P. Arkin

Keyword(s):

Gene Therapy ◽

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Antiretroviral Drugs ◽

Set Point ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Recent reports confirm that, due to the presence of long-lived, latently infected cell populations, eradication of human immunodeficiency virus type 1 (HIV-1) from infected patients by using antiretroviral drugs will be exceedingly difficult. An alternative to virus eradication may be to use gene therapy to induce a pseudo-latent state in virus-producing cells, thus transforming HIV-1 into a lifelong, but manageable, virus. Conditionally replicating HIV-1 (crHIV-1) gene therapy vectors provide an avenue for subduing HIV-1 expression in infected cells (by creating a parasite, crHIV-1, of the parasite HIV-1), potentially reducing the HIV-1 set point and delaying AIDS onset. Development of crHIV-1 vectors has proceeded in vitro, but the requirements for a crHIV-1 vector to proliferate and persist in vivo have not been explored. We expand a widely accepted mathematical model of HIV-1 in vivo dynamics to include a crHIV-1 gene therapy virus and derive a simple criterion for designing crHIV-1 viruses that will persist in vivo. The model introduces only two new parameters—HIV-1 inhibition and crHIV-1 production—and both can be experimentally engineered and controlled. Analysis demonstrates that crHIV-1 gene therapy can indefinitely reduce HIV-1 set point to levels comparable to those achieved with highly active antiretroviral therapy, provided crHIV-1 production is more efficient than HIV-1. Paradoxically, highly efficient therapeutic inhibition of HIV-1 was found to be disadvantageous. Thus, the field may benefit by shifting the search for more potent antiviral genes toward engineering optimized therapy viruses that package ultraefficiently while downregulating viral production moderately.

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Novel Human Immunodeficiency Virus Type 1 Protease Mutations Potentially Involved in Resistance to Protease Inhibitors

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.5.2015-2025.2005 ◽

2005 ◽

Vol 49 (5) ◽

pp. 2015-2025 ◽

Cited By ~ 37

Author(s):

Valentina Svicher ◽

Francesca Ceccherini-Silberstein ◽

Fulvio Erba ◽

Maria Santoro ◽

Caterina Gori ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Local Environment ◽

Antiretroviral Drugs ◽

Resistance Mutations ◽

Genetic Barrier ◽

Immunodeficiency Virus ◽

Definition Of

ABSTRACT Plasma-derived sequences of human immunodeficiency virus type 1 (HIV-1) protease from 1,162 patients (457 drug-naïve patients and 705 patients receiving protease inhibitor [PI]-containing antiretroviral regimens) led to the identification and characterization of 17 novel protease mutations potentially associated with resistance to PIs. Fourteen mutations were positively associated with PIs and significantly correlated in pairs and/or clusters with known PI resistance mutations, suggesting their contribution to PI resistance. In particular, E34Q, K43T, and K55R, which were associated with lopinavir treatment, correlated with mutations associated with lopinavir resistance (E34Q with either L33F or F53L, or K43T with I54A) or clustered with multi-PI resistance mutations (K43T with V82A and I54V or V82A, V32I, and I47V, or K55R with V82A, I54V, and M46I). On the other hand, C95F, which was associated with treatment with saquinavir and indinavir, was highly expressed in clusters with either L90M and I93L or V82A and G48V. K45R and K20T, which were associated with nelfinavir treatment, were specifically associated with D30N and N88D and with L90M, respectively. Structural analysis showed that several correlated positions were within 8 Å of each other, confirming the role of the local environment for interactions among mutations. We also identified three protease mutations (T12A, L63Q, and H69N) whose frequencies significantly decreased in PI-treated patients compared with that in drug-naïve patients. They never showed positive correlations with PI resistance mutations; if anything, H69N showed a negative correlation with the compensatory mutations M36I and L10I. These mutations may prevent the appearance of PI resistance mutations, thus increasing the genetic barrier to PI resistance. Overall, our study contributes to a better definition of protease mutational patterns that regulate PI resistance and strongly suggests that other (novel) mutations beyond those currently known to confer resistance should be taken into account to better predict resistance to antiretroviral drugs.

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Predicting the Impact of Blocking Human Immunodeficiency Virus Type 1 Nef In Vivo

Journal of Virology ◽

10.1128/jvi.00821-08 ◽

2008 ◽

Vol 83 (5) ◽

pp. 2349-2356 ◽

Cited By ~ 5

Author(s):

W. David Wick ◽

Peter B. Gilbert ◽

Otto O. Yang

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Antiretroviral Drugs ◽

Mhc I ◽

Immunodeficiency Virus ◽

The Impact ◽

Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) Nef is a multifunctional protein that confers an ability to evade killing by cytotoxic T lymphocytes (CTLs) as well as other advantages to the virus in vivo. Here we exploited mathematical modeling and related statistical methods to estimate the impact of Nef activity on viral replication in vivo in relation to CTLs. Our results indicate that downregulation of major histocompatibility complex class I (MHC-I) A and B by wild-type Nef confers an advantage to the virus of about 82% in decreased CTL killing efficiency on average, meaning that abolishing the MHC-I downregulation function of Nef would increase killing by more than fivefold. We incorporated this estimate, as well as prior estimates of replicative enhancement by Nef, into a previously published model of HIV-1 and CTLs in vivo (W. D. Wick, O. O. Yang, L. Corey, and S. G. Self, J. Virol. 79:13579-13586, 2005), generalized to permit CTL recognition of multiple epitopes. A sequence database analysis revealed that 92.9% of HIV-1 epitopes are A or B restricted, and a previous study found an average of about 19 epitopes recognized (M. M. Addo et al., J. Virol. 77:2081-2092, 2003). We combined these estimates in the model in order to predict the impact of inhibiting Nef function in the general (chronically infected) population by a drug. The predicted impact on viral load ranged from negligible to 2.4 orders of magnitude, depending on the effects of the drug and the CTL dynamical scenario assumed. We conclude that inhibiting Nef could make a substantial reduction in disease burden, lengthening the time before the necessity of undertaking combination therapy with other antiretroviral drugs.

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Comparison between Sequence Analysis and a Line Probe Assay for Testing Genotypic Resistance of Human Immunodeficiency Virus Type 1 to Antiretroviral Drugs

Journal of Clinical Microbiology ◽

10.1128/jcm.43.8.4186-4188.2005 ◽

2005 ◽

Vol 43 (8) ◽

pp. 4186-4188 ◽

Cited By ~ 3

Author(s):

S. Garcia-Bujalance ◽

C. L. de Guevara ◽

J. Gonzalez-Garcia ◽

J. R. Arribas ◽

A. Gutierrez

Keyword(s):

Human Immunodeficiency Virus ◽

Sequence Analysis ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Antiretroviral Drugs ◽

Line Probe Assay ◽

Genotypic Resistance ◽

Immunodeficiency Virus ◽

Probe Assay

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Lack of Effect of Recombinant Human Growth Hormone on the In Vitro Activities of Antiretroviral Drugs against Human Immunodeficiency Virus Type 1

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.48.6.2337-2340.2004 ◽

2004 ◽

Vol 48 (6) ◽

pp. 2337-2340 ◽

Cited By ~ 2

Author(s):

Mark A Wainberg ◽

Bluma G. Brenner ◽

Eric Daar ◽

Joseph M. Gertner ◽

Clement Olivier ◽

...

Keyword(s):

Growth Hormone ◽

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Human Growth Hormone ◽

Recombinant Human Growth Hormone ◽

Human Growth ◽

Antiretroviral Drugs ◽

Immunodeficiency Virus

ABSTRACT We studied the effects of recombinant human growth hormone (r-hGH) on human immunodeficiency virus type 1 replication by growing both wild-type and drug-resistant variants of virus in the presence of various concentrations of eight different antiretroviral drugs. r-hGH had no significant effect on either viral replication or the 50% inhibitory concentrations of these compounds.

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Amino Acid Substitutions at Position 190 of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Increase Susceptibility to Delavirdine and Impair Virus Replication

Journal of Virology ◽

10.1128/jvi.77.2.1512-1523.2003 ◽

2003 ◽

Vol 77 (2) ◽

pp. 1512-1523 ◽

Cited By ~ 71

Author(s):

Wei Huang ◽

Andrea Gamarnik ◽

Kay Limoli ◽

Christos J. Petropoulos ◽

Jeannette M. Whitcomb

Keyword(s):

Human Immunodeficiency Virus ◽

Amino Acid ◽

Reverse Transcriptase ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Antiretroviral Drugs ◽

Replication Capacity ◽

Amino Acid Substitutions ◽

Immunodeficiency Virus

ABSTRACT Suboptimal treatment of human immunodeficiency virus type 1 (HIV-1) infection with nonnucleoside reverse transcriptase inhibitors (NNRTI) often results in the rapid selection of drug-resistant virus. Several amino acid substitutions at position 190 of reverse transcriptase (RT) have been associated with reduced susceptibility to the NNRTI, especially nevirapine (NVP) and efavirenz (EFV). In the present study, the effects of various 190 substitutions observed in viruses obtained from NNRTI-experienced patients were characterized with patient-derived HIV isolates and confirmed with a panel of isogenic viruses. Compared to wild-type HIV, which has a glycine at position 190 (G190), viruses with 190 substitutions (A, C, Q, S, V, E, or T, collectively referred to as G190X substitutions) were markedly less susceptible to NVP and EFV. In contrast, delavirdine (DLV) susceptibility of these G190X viruses increased from 3 to 300-fold (hypersusceptible) or was only slightly decreased. The replication capacity of viruses with certain 190 substitutions (C, Q, V, T, and E) was severely impaired and was correlated with reduced virion-associated RT activity and incomplete protease (PR) processing of the viral p55 gag polyprotein. These defects were the result of inadequate p160 gagpol incorporation into virions. Compensatory mutations within RT and PR improved replication capacity, p55 gag processing, and RT activity, presumably through increased incorporation of p160 gagpol into virions. We observe an inverse relationship between the degree of NVP and EFV resistance and the impairment of viral replication in viruses with substitutions at 190 in RT. These observations may have important implications for the future design and development of antiretroviral drugs that restrict the outgrowth of resistant variants with high replication capacity.

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Contribution of Immune Activation to the Pathogenesis and Transmission of Human Immunodeficiency Virus Type 1 Infection

Clinical Microbiology Reviews ◽

10.1128/cmr.14.4.753-777.2001 ◽

2001 ◽

Vol 14 (4) ◽

pp. 753-777 ◽

Cited By ~ 180

Author(s):

Stephen D. Lawn ◽

Salvatore T. Butera ◽

Thomas M. Folks

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Immune Activation ◽

Antiretroviral Drugs ◽

Host Cells ◽

Immunodeficiency Virus ◽

Hiv 1

SUMMARY The life cycle of human immunodeficiency virus type 1 (HIV-1) is intricately related to the activation state of the host cells supporting viral replication. Although cellular activation is essential to mount an effective host immune response to invading pathogens, paradoxically the marked systemic immune activation that accompanies HIV-1 infection in vivo may play an important role in sustaining phenomenal rates of HIV-1 replication in infected persons. Moreover, by inducing CD4+ cell loss by apoptosis, immune activation may further be central to the increased rate of CD4+ cell turnover and eventual development of CD4+ lymphocytopenia. In addition to HIV-1-induced immune activation, exogenous immune stimuli such as opportunistic infections may further impact the rate of HIV-1 replication systemically or at localized anatomical sites. Such stimuli may also lead to genotypic and phenotypic changes in the virus pool. Together, these various immunological effects on the biology of HIV-1 may potentially enhance disease progression in HIV-infected persons and may ultimately outweigh the beneficial aspects of antiviral immune responses. This may be particularly important for those living in developing countries, where there is little or no access to antiretroviral drugs and where frequent exposure to pathogenic organisms sustains a chronically heightened state of immune activation. Moreover, immune activation associated with sexually transmitted diseases, chorioamnionitis, and mastitis may have important local effects on HIV-1 replication that may increase the risk of sexual or mother-to-child transmission of HIV-1. The aim of this paper is to provide a broad review of the interrelationship between immune activation and the immunopathogenesis, transmission, progression, and treatment of HIV-1 infection in vivo.

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