What are the Human Immunodeficiency Virus (HIV) resistance genes?

From the Guidelines

HIV resistant genes are primarily categorized into acquired drug resistance, transmitted drug resistance, and pre-treatment drug resistance, with the latter being most concerning in a public health context where ART is provided without individual HIVDR testing. The emergence of HIV drug resistance over time remains a public health challenge, despite the scale-up of Antiretroviral Therapy (ART) and new recommendations for testing and treatment 1. Some individuals possess genetic mutations that provide resistance to HIV infection or slow disease progression, such as the CCR5-delta32 mutation, which alters the CCR5 receptor on immune cells that HIV typically uses to enter and infect cells 1. Key points to consider include:

• Acquired drug resistance (ADR) occurs when drug resistance is selected for in an individual receiving antiretroviral drugs with sub-optimal dosing or poor adherence
• Transmitted drug resistance (TDR) occurs when a drug-naïve individual is infected with a drug-resistant virus
• Pre-treatment drug resistance (PDR) is drug resistance detected at the time of ART initiation or re-initiation
• Natural drug resistance occurs in HIV type 2 and in HIV-1 groups N and O, due to pre-existing polymorphisms conferring innate resistance to certain drugs The use of integrase inhibitor-based ART, specifically dolutegravir-based ART, may reduce the relevance of PDR, as it is less susceptible to resistance mutations 1. National and regional genotyping surveillance are crucial in identifying and managing drug resistance, particularly in low- and middle-income countries where individual HIVDR testing is not commonly performed 1. Sound surveillance of HIV drug resistance requires knowledge of the affected populations and how resistance to drugs and drug classes emerges, as well as assessing trends in prevalence or incidence of HIVDR over time 1.

From the FDA Drug Label

FTC-resistant isolates of HIV-1 have been selected in cell culture and in vivo. Genotypic analysis of these isolates showed that the reduced susceptibility to FTC was associated with a valine or isoleucine (M184V/I) substitution in the HIV-1 RT The M184V amino acid substitution, associated with resistance to emtricitabine and 3TC, was observed in 2/19 analyzed subject isolates in the emtricitabine + TDF group and in 10/29 analyzed subject isolates in the AZT/3TC group. Cross-resistance among certain NRTIs has been recognized. FTC-resistant isolates (M184V/I) were cross-resistant to 3TC but retained susceptibility in cell culture to AZT, didanosine, d4T, and tenofovir, and to NNRTIs (delavirdine, EFV, and nevirapine)

HIV Resistant Genes:

• The main genes associated with resistance to emtricitabine are M184V/I substitutions in the HIV-1 RT.
• These genes are also associated with cross-resistance to 3TC.
• However, FTC-resistant isolates retain susceptibility to AZT, didanosine, d4T, tenofovir, and NNRTIs such as delavirdine, EFV, and nevirapine.
• The K65R substitution, selected in vivo by abacavir, didanosine, and tenofovir, demonstrates reduced susceptibility to inhibition by FTC.
• Other substitutions such as M41L, D67N, K70R, L210W, T215Y/F, K219Q/E (associated with resistance to AZT and d4T), and L74V (associated with resistance to didanosine), do not affect susceptibility to FTC.
• The K103N substitution, associated with resistance to NNRTIs, also does not affect susceptibility to FTC 2

From the Research

HIV Resistant Genes

• The CCR5 gene is a key factor in HIV infection, with a homozygous Δ32 mutation in the CCR5 gene preventing CCR5 cell surface expression and conferring resistance to infection with CCR5-tropic HIV strains 3.
• Individuals with the CCR5Δ32/Δ32 genotype have been shown to have near-complete resistance to HIV infection, irrespective of exposure 4.
• The CCR5Δ32 mutation has been implicated in the development of curative HIV therapy, with transplantation of hematopoietic stem cells from a CCR5Δ32/Δ32 donor resulting in the elimination of HIV from the recipient's immune system 3, 5.
• The use of CCR5 inhibitors, such as maraviroc, has been shown to be effective in reducing HIV RNA levels and improving mucosal immunity in HIV-infected patients 6.
• The CCR5 gene has also been implicated in regulating infection with other pathogens, including Staphylococcus aureus, and in recovery from stroke and graft versus host disease (GVHD) in cancer transplant patients 4.

Mechanism of Resistance

• The CCR5Δ32 mutation prevents CCR5 cell surface expression, thereby blocking HIV entry into host cells 3, 4.
• The mechanism of resistance conferred by the CCR5Δ32 mutation is thought to be due to the lack of CCR5 expression on the surface of host cells, making it difficult for HIV to bind and enter the cells 3, 4.
• The use of CCR5 inhibitors, such as maraviroc, works by blocking the CCR5 receptor, preventing HIV from binding and entering host cells 6.

Clinical Implications

• The discovery of the CCR5Δ32 mutation has led to the development of curative HIV therapy, with transplantation of hematopoietic stem cells from a CCR5Δ32/Δ32 donor resulting in the elimination of HIV from the recipient's immune system 3, 5.
• The use of CCR5 inhibitors, such as maraviroc, has been shown to be effective in reducing HIV RNA levels and improving mucosal immunity in HIV-infected patients 6.
• The CCR5 gene has also been implicated in regulating infection with other pathogens, including Staphylococcus aureus, and in recovery from stroke and graft versus host disease (GVHD) in cancer transplant patients 4.