scholarly journals Mutations That Confer Resistance to Template-Analog Inhibitors of Human Immunodeficiency Virus (HIV) Type 1 Reverse Transcriptase Lead to Severe Defects in HIV Replication

2002 ◽  
Vol 76 (8) ◽  
pp. 4068-4072 ◽  
Author(s):  
Timothy S. Fisher ◽  
Pheroze Joshi ◽  
Vinayaka R. Prasad
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Dna Aptamer ◽  
Hiv Replication ◽  
Immunodeficiency Virus ◽  
Hiv Type 1 ◽  
High Level ◽  
Level Resistance

ABSTRACT We isolated two template analog reverse transcriptase (RT) inhibitor-resistant mutants of human immunodeficiency virus (HIV) type 1 RT by using the DNA aptamer, RT1t49. The mutations associated, N255D or N265D, displayed low-level resistance to RT1t49, while high-level resistance could be observed when both mutations were present (Dbl). Molecular clones of HIV that contained the mutations produced replication-defective virions. All three RT mutants displayed severe processivity defects. Thus, while biochemical resistance to the DNA aptamer RT1t49 can be generated in vitro via multiple mutations, the overlap between the aptamer- and template-primer-binding pockets favors mutations that also affect the RT-template-primer interaction. Therefore, viruses with such mutations are replication defective. Potent inhibition and a built-in mechanism to render aptamer-resistant viruses replication defective make this an attractive class of inhibitors.

scholarly journals High-Level Resistance to 3′-Azido-3′-Deoxythimidine due to a Deletion in the Reverse Transcriptase Gene of Human Immunodeficiency Virus Type 1

2000 ◽  
Vol 74 (2) ◽  
pp. 1023-1028 ◽  
Author(s):  
Tomozumi Imamichi ◽  
Tanima Sinha ◽  
Hiromi Imamichi ◽  
Yi-Ming Zhang ◽  
Julie A. Metcalf ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Immunodeficiency Virus ◽  
Azt Resistance ◽  
High Level ◽  
Level Resistance

ABSTRACT A variant of human immunodeficiency virus type 1 (HIV-1) possessing a deletion in the reverse transcriptase (RT) gene at codon 67 was identified in a patient who had failed combination antiretroviral therapy. This deletion initially emerged under the selective pressure of combination therapy with 3′-azido-3′-deoxythymidine (AZT) plus 2′,3′-dideoxyinosine. It has persisted for more than 3 years in association with the accumulation of a variety of other well-described drug resistance mutations and an uncharacterized mutation at RT codon 69 (T69G). Phenotypic studies demonstrated that the codon 67 deletion by itself had little effect on AZT sensitivity. However, in the context of the T69G mutation and three other mutations known to be associated with AZT resistance (K70R, T215F, and K219Q), this deletion led to a increase in AZT resistance from 8.5-fold to 445-fold. A further increase in resistance (up to 1,813-fold) was observed when two mutations associated with nonnucleoside RT inhibitor resistance (K103N and L74I) were added to the deletion T69G K70R T215F K219Q construct. Hence, these results establish that a deletion at RT codon 67 may be selected for in the presence of antiretroviral therapy and may lead to high-level resistance to AZT.

scholarly journals Immunoglobulin G (IgG) and IgA, but also Nonantibody Factors, Account for In Vitro Neutralization of Human Immunodeficiency Virus (HIV) Type 1 Primary Isolates by Serum and Plasma of HIV-Infected Patients

2001 ◽  
Vol 75 (11) ◽  
pp. 5421-5424 ◽  
Author(s):  
Renaud Burrer ◽  
Dominique Salmon-Ceron ◽  
Sophie Richert ◽  
Gianfranco Pancino ◽  
Gabriella Spiridon ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Broad Spectrum ◽  
Plasma Samples ◽  
Two Samples ◽  
Immunodeficiency Virus ◽  
Hiv Type 1 ◽  
High Level ◽  
Hiv 1

ABSTRACT The factors present in serum and plasma samples of human immunodeficiency virus (HIV)-infected patients that are responsible for the neutralization of four HIV type 1 (HIV-1) primary isolates in vitro have been analyzed. Purification of immunoglobulins (Ig) by affinity chromatography showed that the activities were mostly attributable to IgG and less frequently to IgA. For two samples, we have shown that the high-level and broad-spectrum inhibitory activity was essentially caused by non-Ig factors interfering with the measurement of antibody-specific neutralizing activity.

scholarly journals Impact of Cytokines on Replication in the Thymus of Primary Human Immunodeficiency Virus Type 1 Isolates from Infants

2002 ◽  
Vol 76 (14) ◽  
pp. 6929-6943 ◽  
Author(s):  
Livia Pedroza-Martins ◽  
W. John Boscardin ◽  
Deborah J. Anisman-Posner ◽  
Dominique Schols ◽  
Yvonne J. Bryson ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Disease Progression ◽  
Chemokine Receptors ◽  
Interleukin 2 ◽  
Hiv Replication ◽  
Rapid Disease Progression ◽  
Immunodeficiency Virus ◽  
Hiv Type 1

ABSTRACT Early infection of the thymus with the human immunodeficiency virus (HIV) may explain the more rapid disease progression among children infected in utero than in children infected intrapartum. Therefore, we analyzed infection of thymocytes in vitro by HIV type 1 primary isolates, obtained at or near birth, from 10 children with different disease outcomes. HIV isolates able to replicate in the thymus and impact thymopoiesis were present in all infants, regardless of the timing of viral transmission and the rate of disease progression. Isolates from newborns utilized CCR5, CXCR4, or both chemokine receptors to enter thymocytes. Viral expression was observed in discrete thymocyte subsets postinfection with HIV isolates using CXCR4 (X4) and isolates using CCR5 (R5), despite the wider distribution of CXCR4 in the thymus. In contrast to previous findings, the X4 primary isolates were not more cytopathic for thymocytes than were the R5 isolates. The cytokines interleukin-2 (IL-2), IL-4, and IL-7 increased HIV replication in the thymus by inducing differentiation and expansion of mature CD27+ thymocytes expressing CXCR4 or CCR5. IL-2 and IL-4 together increased expression of CXCR4 and CCR5 in this population, whereas IL-4 and IL-7 increased CXCR4 but not CCR5 expression. IL-2 plus IL-4 increased the viral production of all pediatric isolates, but IL-4 and IL-7 had a significantly higher impact on the replication of X4 isolates compared to R5 isolates. Our studies suggest that coreceptor use by HIV primary isolates is important but is not the sole determinant of HIV pathogenesis in the thymus.

scholarly journals Amino Acid Deletion at Codon 67 and Thr-to-Gly Change at Codon 69 of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Confer Novel Drug Resistance Profiles

2001 ◽  
Vol 75 (8) ◽  
pp. 3988-3992 ◽  
Author(s):  
Tomozumi Imamichi ◽  
Michael A. Murphy ◽  
Hiromi Imamichi ◽  
H. Clifford Lane
Keyword(s):  
Human Immunodeficiency Virus ◽  
Amino Acid ◽  
Reverse Transcriptase ◽  
Amino Acid Deletion ◽  
Hiv Replication ◽  
Immunodeficiency Virus ◽  
Hiv Type 1 ◽  
Replication Fitness ◽  
Novel Drug

ABSTRACT The potential roles of an amino acid deletion at codon 67 (Δ67) and a Thr-to-Gly change at codon 69 (T69G) in the reverse transcriptase of human immunodeficiency virus (HIV) type 1 in drug sensitivity and relative replication fitness were studied. Our results suggest that the Δ67 and T69G changes can be categorized as mutations associated with multidrug resistance. The combination of both mutations with an L74I change (Δ67+T69G/L74I) leads to a novel 3′-azido-3′-deoxythymidine resistance motif and compensates for impaired HIV replication.

scholarly journals Characterization of a Subtype D Human Immunodeficiency Virus Type 1 Isolate That Was Obtained from an Untreated Individual and That Is Highly Resistant to Nonnucleoside Reverse Transcriptase Inhibitors

2004 ◽  
Vol 78 (10) ◽  
pp. 5390-5401 ◽  
Author(s):  
Yong Gao ◽  
Ellen Paxinos ◽  
Justin Galovich ◽  
Ryan Troyer ◽  
Heather Baird ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Cell Cultures ◽  
Wild Type ◽  
Immunodeficiency Virus ◽  
High Level ◽  
Subtype A ◽  
Hiv 1 ◽  
Level Resistance

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) isolates derived from HIV-infected, treatment-naive Ugandan infants were propagated and tested for sensitivity to antiretroviral (ARV) drugs. Although most subtype A and D isolates displayed inhibition profiles similar to those of subtype B strains, a subtype D isolate identified as D14-UG displayed high-level resistance to nevirapine in peripheral blood mononuclear cell cultures (>2,000-fold) and in MT4 cell cultures (∼800-fold) but weaker resistance to delavirdine (∼13-fold) and efavirenz (∼8-fold) in MT4 cell cultures. To investigate the possible mechanism for this resistance to nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs), the RT coding region in pol was sequenced and compared to the consensus RT sequence of NNRTI-resistant and NNRTI-sensitive subtype A, B, and D HIV-1 isolates. D14-UG did not contain the classic amino acid substitutions conferring NNRTI resistance (e.g., Y181C, K103N, and G190A) but did have some putative sites associated with drug resistance, I135L, T139V, and V245T. Wild-type and mutated protease-RT genes from D14-UG and an NNRTI-sensitive subtype D isolate from Uganda (D13-UG) were cloned into pNL4-3 to produce recombinant viruses and to determine the effects of the mutations on susceptibility to ARV drugs, specifically, NNRTIs. The results showed that I135L and/or V245T mutations can confer high-level resistance to nevirapine and delavirdine as well as low level cross-resistance to efavirenz. Finally, ex vivo fitness analyses suggested that NNRTI-resistant sites 135L and 245T in wild-type isolate D14-UG may reduce RT fitness but do not have an impact on the fitness of the primary HIV-1 isolate.

An Approach towards the Synthesis of Potential Metal-Chelating TSAO-T Derivatives as Bidentate Inhibitors of Human Immunodeficiency virus Type 1 Reverse Transcriptase

1998 ◽  
Vol 9 (5) ◽  
pp. 412-421 ◽  
Author(s):  
C Chamorro ◽  
M-J Camarasa ◽  
M-J Pérez-Pérez ◽  
E de Clercq ◽  
J Balzarini ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Parent Compound ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

Novel derivatives of the potent human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitor TSAO-T have been designed, synthesized and tested for their in vitro antiretro-viral activity against HIV. These TSAO-T derivatives have been designed as potential bidentate inhibitors of HIV-1 RT, which combine in their structure the functionality of a non-nucleoside RT inhibitor (TSAO-T) and a bivalent ion-chelating moiety (a β-diketone moiety) linked through an appropriate spacer to the N-3 of thymine of TSAO-T . Some of the new compounds have an anti-HIV-1 activity comparable to that of the parent compound TSAO-T, but display a markedly increased antiviral selectivity. There was a clear relationship between antiviral activity and the length of the spacer group that links the TSAO molecule with the chelating moiety. A shorter spacer invariably resulted in increased antiviral potency. None of the TSAO-T derivatives were endowed with anti-HIV-2 activity.

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