SARS-CoV-2 prolonged infection during advanced HIV disease evolves extensive immune escape

Abstract

Characterizing SARS-CoV-2 evolution in specific geographies may help predict properties of the variants that come from these regions. We mapped neutralization of a SARS-CoV-2 strain that evolved over 6 months from ancestral virus in a person with advanced HIV disease in South Africa; this person was infected prior to emergence of the Beta and Delta variants. We longitudinally tracked the evolved virus and tested it against self-plasma and convalescent plasma from ancestral, Beta, and Delta infections. Early virus was similar to ancestral, but it evolved a multitude of mutations found in Omicron and other variants. It showed substantial but incomplete Pfizer BNT162b2 escape, weak neutralization by self-plasma, and despite pre-dating Delta, it also showed extensive escape of Delta infection-elicited neutralization. This example is consistent with the notion that SARS-CoV-2 evolving in individual immune-compromised hosts, including those with advanced HIV disease, may gain immune escape of vaccines and enhanced escape of Delta immunity, and this has implications for vaccine breakthrough and reinfections.

Keywords: Beta variant; Delta variant; HIV; SARS-CoV-2; advanced HIV disease; evolution; immune escape; neutralization; variants of concern.

Graphical abstract

Figure 1

Neutralization distance between variants (A) Infection waves and variant frequencies in South Africa. (B) Maximum-likelihood phylogenetic tree with evolved virus sequences (red) at six time points in relation to 3,883 global sequences with variants shown. (C–E) Neutralization of the Beta (C), Delta (D), and Alpha (E) virus compared to D614G ancestral virus by plasma from convalescent participants infected by ancestral strains (n = 8). (F–G) Neutralization of the Delta (F) and Alpha (G) virus compared to Beta virus by plasma from Beta infections (n = 9). (H–I) Neutralization of the Beta (H) and Alpha (I) viruses compared to Delta virus by plasma from Delta infections (n = 10). Experiments presented in panels C–I performed using a live virus neutralization assay (LVNA). (J) Neutralization of Beta compared to Delta virus with the same plasma as (I) using a pseudo-virus neutralization assay (PNA). Red horizontal line denotes most concentrated plasma tested. Numbers in black above each virus strain are geometric mean titers (GMT) of the reciprocal plasma dilution (FRNT₅₀ for LVNA, ID₅₀ for PNA) for 50% neutralization. Numbers in red denote fold-change in GMT between virus strain on the left and the virus strain on the right. p values are ^∗<0.05–0.01, ^∗∗<0.01–0.001, ^∗∗∗<0.001–0.0001, and ^∗∗∗∗<0.0001 as determined by the Wilcoxon rank sum test.

Figure 2

Mapping neutralization of variants and evolved virus (A) Participant characteristics over 233 days from SARS-CoV-2 diagnosis: CD4 T cell count (cells/μL), SARS-CoV-2 detection by qPCR, virus outgrowth success, and presence of anti-RBD IgG. Because IgG levels were close to the background for some time points, they were marked as borderline. (B) Majority and minority SARS-CoV-2 genotypes in the swab (day 0) and outgrowth (day 6 to 190). X axis lists substitutions and deletions in spike sequence, and positions where mutations are found in variants are highlighted. AF: allele frequency. (C) Cryogenic electron microscopy (cryo-EM) structure of the SARS-CoV-2 spike protein. The mutations in day 190 isolated virus (D190) shown as red spheres. (D) Neutralization of day 6 isolated (D6), day 20 isolated (D20), and D190 virus by self-plasma collected days 6 to 216 and the ancestral D614G, Beta, and Delta viruses with plasma collected day 216. (E-F) Neutralization of D6 (E) and D20 (F) relative to D190 virus by ancestral-infection-elicited plasma (n = 8). (G) Neutralization of D190 compared to D614G by Pfizer BNT162b2 plasma (n = 12). (H-I) Neutralization of D190 (H) and D6 (I) compared to D614G by ancestral plasma (n = 8). (J-K) Neutralization of D190 (J) and D6 (K) compared to Beta virus by Beta plasma (n = 9). (L-M) Neutralization of D190 (L) and D6 (M) compared to Delta virus by Delta plasma (n = 10). Red horizontal line denotes most concentrated plasma tested. Numbers in black are GMT FRNT₅₀. Numbers in red are fold-change in GMT between virus strain on left and right. p values are ^∗<0.05–0.01, ^∗∗<0.01–0.001, and ^∗∗∗<0.001–0.0001 as determined by the Wilcoxon rank sum test. (N) Summary map (not to scale) of serological distances as measured by fold-decrease in neutralization. For clarity, Beta plasma neutralization of D6 is not shown.