New antiretroviral inhibitors and HIV-1 drug resistance: more focus on 90% HIV-1 isolates?

Abstract

Combined HIV antiretroviral therapy (cART) has been effective except if drug resistance emerges. As cART has been rolled out in low-income countries, drug resistance has emerged at higher rates than observed in high income countries due to factors including initial use of these less tolerated cART regimens, intermittent disruptions in drug supply, and insufficient treatment monitoring. These socioeconomic factors impacting drug resistance are compounded by viral mechanistic differences by divergent HIV-1 non-B subtypes compared to HIV-1 subtype B that largely infects the high-income countries (just 10% of 37 million infected). This review compares the inhibition and resistance of diverse HIV-1 subtypes and strains to the various approved drugs as well as novel inhibitors in clinical trials. Initial sequence variations and differences in replicative fitness between HIV-1 subtypes pushes strains through different fitness landscapes to escape from drug selective pressure. The discussions here provide insight to patient care givers and policy makers on how best to use currently approved ART options and reduce the emergence of drug resistance in ∼33 million individuals infected with HIV-1 subtype A, C, D, G, and recombinants forms. Unfortunately, over 98% of the literature on cART resistance relates to HIV-1 subtype B.

Keywords: HIV-1 genetic diversity; HIV-1 subtype specific resistance; antiretroviral therapy; discovery of novel HIV inhibitors; low-and middle-income countries; non-subtype B HIV-1.

Figure 1.

FDA-approved HIV-1 treatment drugs and combinations.(A) Regimens approved for HIV-1 treatment: blue, NRTIs; orange, NNRTIs; green, PIs; red, INSTIs; yellow, pharmacokinetic enhancers; pink, post-attachment inhibitors; and black, fusion inhibitors. (B) Brand names of approved oral and injectable ART combinations with respective drug abbreviations: blue, combinations consisting of reverse transcriptase inhibitors; green, combinations of PIs; red, combination of INSTIs and NNRTIs; black, combinations with more than one class of drug.

Figure 2.

Distribution of dominant HIV-1 subtypes by region. The color presentation of different HIV-1 subtypes is embedded in the figure.

Figure 3.

Adult antiretroviral use in first- and second-line therapies in LMICs. (A) Status of dolutegravir uptake in LMICs as of July 2020. (B) Estimated use of NNRTI/INSTIs and (C) NRTIs as components of adult first-line therapies in generic accessible-LMICs. (D) Use of PIs as components of adult second-line therapies in LMICs.

Figure 4.

Sensitivity of HIV-1 Primary Isolates to Maraviroc. (A) IC50 values of a panel of HIV-1 group M viruses from primary isolates including subtype A (red), subtype B (blue), subtype C (grey), and subtype D (green) to maraviroc were determined in U87.CD4.CCR5 cells at a multiplicity of infection of 0.01 IU/cell. Alignments of the V3 loop region of gp120 with reference virus HXB2 are also shown. (B) Drug sensitivity curves of V3 loop chimeric NL4-3 viruses generated from primary isolates in Fig. 4A were performed in U87.CD4.CCR5 cells. Data represents triplicates with standard deviations shown.

Figure 5.

The chemical structures of approved INSTIs. The coplanar oxygen atoms are highlighted in red; green circles highlight extended linkers, which are a common feature of all second-generation INSTIs.

Figure 6.

HIV-1 integrase variability among different subtypes. Across the HIV-1 integrase gene, there are several differences in naturally occurring polymorphisms in different HIV-1 subtypes. These polymorphisms may function as compensatory mutations in specific subtypes which may influence differential selection of major mutations. HIV-1 integrase sequences of cART naïve patients were downloaded from HIV-1 sequence database (http://www.HIV-1.lanl.gov/). Blue rectangular boxes show the three catalytic triad residues of CCD (D64, D116, and E152), green- major resistance mutation positions and red-polymorphisms naturally occurring between different HIV-1 subtypes. General consensus of amino acids at a particular position between HIV-1 subtypes is represented by (.).

Figure 7.

The variability of HIV-1 gp120 amino acid residues at the binding site of BMS- 626529. The HIV-1 gp120 amino acid residues within 5 Å (A) and 3.5 Å (B) of the inhibitor are shown. The carbon atoms of BMS-626529 are depicted in yellow, nitrogen in blue, and oxygen in red. The highly variable amino acid residues S375, M426, M434, and M475 are shown in violet and hydrogen bonds in bright orange. (C) Alignment of HIV-1 gp120 consensus sequences from HIV-1 cART naïve patients, subtype A1 (n = 231), A6 (n = 71), B (n = 6619), C (n = 5516), D (n = 179), G (n = 40), CRF01_AE (n = 1355), CRF02-AG (n = 206), and CRF07_BC (n = 338). The sequences were downloaded from the Los Alamos HIV-1 sequence database and coordinates of HXB2 (K03455) were used to make the alignments.

Figure 8.

The variability of HIV-1 gp120 consensus sequences between HIV-1 subtype B and CRF01_AE. The codon sequences coding for temsavir active site amino acids 375, 426, 434, and 475 are boxed in green. The subtype B (n = 6619) and CRF01_AE (n = 1355) gp120 sequences from HIV cART naïve patients were downloaded from the Los Alamos HIV sequence database and sequence position coordinates of the HXB2 sequence (K03455) were used to make the alignments.

Figure 9.

HIV-1 CA and GS-6207 complex. X-ray crystal structure of GS-6207-CA (PDB ID 6V2F) (Link et al. 2020) shows novel capsid inhibitor GS-6207 binding between NTD of one CA monomer (cyan) and CTD of a neighboring monomer (dark blue) to interfere with assembly and disassembly of HIV-1, leading to production of non-infectious virions. (A) GS-6207, depicted in magenta, interacts with residues (orange) N57, K70, N74 of the CA-NTD monomer, as well as Q179 and N183 of the adjacent CA-CTD monomer. (B) The residues associated with resistance against GS-6207 are depicted in orange (L56, Q67, M66, N74, A105) and are localised at the active site of GS-6207.