Sequence variability associated with human immunodeficiency virus type 1 (HIV-1) is useful for inferring structural and/or functional constraints at specific residues within the viral protease. Positions that are invariant even in the presence of drug selection define critically important residues for protease function. While the importance of conserved active-site residues is easily understood, the role of other invariant residues is not. This work focuses on invariant Thr80 at the apex of the P1 loop of HIV-1, HIV-2, and simian immunodeficiency virus protease. In a previous study, we postulated, on the basis of a molecular dynamics simulation of the unliganded protease, that Thr80 may play a role in the mobility of the flaps of protease. In the present study, both experimental and computational methods were used to study the role of Thr80 in HIV protease. Three protease variants (T80V, T80N, and T80S) were examined for changes in structure, dynamics, enzymatic activity, affinity for protease inhibitors, and viral infectivity. While all three variants were structurally similar to the wild type, only T80S was functionally similar. Both T80V and T80N had decreased the affinity for saquinavir. T80V significantly decreased the ability of the enzyme to cleave a peptide substrate but maintained infectivity, while T80N abolished both activity and viral infectivity. Additionally, T80N decreased the conformational flexibility of the flap region, as observed by simulations of molecular dynamics. Taken together, these data indicate that HIV-1 protease functions best when residue 80 is a small polar residue and that mutations to other amino acids significantly impair enzyme function, possibly by affecting the flexibility of the flap domain.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1489026PMC
http://dx.doi.org/10.1128/JVI.01900-05DOI Listing

Publication Analysis

Top Keywords

immunodeficiency virus
12
viral infectivity
12
protease
10
role invariant
8
invariant thr80
8
human immunodeficiency
8
virus type
8
molecular dynamics
8
t80v t80n
8
t80n decreased
8

Similar Publications

Introduction: Coronavirus Disease 19 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), and Human Immunodeficiency Virus (HIV) are significant 21st-century pandemics with distinct virological and clinical characteristics. COVID-19 primarily presents as an acute respiratory illness, while HIV leads to chronic immune suppression. Understanding their differences can enhance public health strategies and treatment approaches.

View Article and Find Full Text PDF

Pneumocystis Jirovecii Pneumonia in Two Immunosuppressed Non-HIV Infected Patients: A Clinical and Therapeutic Analysis.

Infect Drug Resist

January 2025

Department of Clinical Medicine, School of Medicine, Qinghai University, Xining, People's Republic of China.

Pneumocystis jirovecii pneumonia (PJP) is an opportunistic fungal infection that often occurs secondary to human immunodeficiency virus (HIV) infection. However, for non-HIV immunocompromised patients, such as those undergoing novel immunosuppressive treatments to manage malignancies, organ transplants, or connective tissue diseases, PJP is emerging as an increasing threat. The clinical manifestations of PJP in HIV-infected and non-HIV-infected patients differ significantly.

View Article and Find Full Text PDF

Current methods for detecting and assessing HIV-1 antibody resistance.

Front Immunol

January 2025

Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

Antiretroviral therapy is the standard treatment for HIV, but it requires daily use and can cause side effects. Despite being available for decades, there are still 1.5 million new infections and 700,000 deaths each year, highlighting the need for better therapies.

View Article and Find Full Text PDF

Coccidioidal meningitis is a rare yet life-threatening complication of disseminated infection, primarily affecting immunocompromised individuals.  and  are dimorphic fungi endemic to the southwestern United States, where exposure to inhaled spores can lead to a range of clinical manifestations, including pulmonary and central nervous system (CNS) involvement. This report describes the case of a 27-year-old correctional officer with advanced human immunodeficiency virus (HIV) infection who presented with chronic headaches, altered mental status, and significant weight loss following his relocation from Arizona to Louisiana.

View Article and Find Full Text PDF

Case report: a 3-year follow-up on nodal marginal zone lymphoma coexisting with disseminated Talaromyces marneffei infection in a non-endemic area.

Front Oncol

January 2025

Department of Pathology, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Zhejiang, Yiwu, China.

This case report presents the details of an elderly man in Zhejiang Province of China, who tested human immunodeficiency virus (HIV) negative and subsequently developed Nodal Marginal Zone Lymphoma (NMZL) along with disseminated infection. The study focuses on analyzing the distinct clinical symptoms and pathological manifestations in order to offer precise diagnosis and effective treatment for patients. A 76-year-old male patient was admitted to our hospital due to recurrent fever.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!