Human immunodeficiency virus type 1 primary isolate neutralization resistance is associated with the syncytium-inducing phenotype and lower CD4 cell counts in subtype CRF01_AE-infected patients

Abstract

A number of human immunodeficiency virus type 1 (HIV-1) non-B-subtype products have been developed for present or future vaccine trials; in Thailand, several studies using subtype B and/or CRF01_AE vaccines have been conducted. To better characterize the biologic properties of these subtypes, 70 HIV-1 subtype B and E isolates were phenotyped as syncytium-inducing (SI) or non-syncytium-inducing (NSI) isolates and assessed for sensitivity to neutralizing antibody (NAb). A significantly higher number of NSI subtype E viruses were neutralization sensitive than SI subtype E viruses (P = 0.009), while no association between viral phenotype and sensitivity to NAb was observed for subtype B (P = 0.856), suggesting a difference in the neutralization patterns of subtypes B and E. Strikingly, concurrent CD4 T-cell numbers were significantly lower for subtype E-infected patients whose isolates were more resistant to NAb, both for the overall study group (P < 0.001) as well as for the 22 patients with NSI isolates (P = 0.013). Characterization of the evolution of biologic properties of both B and non-B HIV-1 subtypes will provide a clearer understanding of the repertoire of antibodies that must be elicited for a vaccine to be effective against all phenotypes and subtypes.

FIG. 1.

The percentages of neutralization for each of three NAb pools are indicated. For subtype E viruses, the B pool with the highest percent neutralization is listed in the Bp column; for subtype B viruses, the data for the most potent E pool are shown under the Ep columns. Values of ≥84% (within the upper [4th] quartile of the distribution of data for all E NAb-E virus neutralization pairs) are indicated by red squares, while <84% neutralization is indicated by white squares. Viruses that were strongly neutralized (≥84%) by at least one pool were considered sensitive. These data represent the mean of two to six experiments (in quadruplicate) for each virus; the patient CD4 cell numbers coincident with virus isolation are indicated for subtype E isolates. CD4 counts of <200 are in bold and italicized (panels A and B). NA, data not available.

FIG. 2.

Neutralization of sensitive versus resistant subtype E viruses using pooled and individual subtype E-infected patient plasmas. The percentages of neutralization by the two E NAb pools, as well as by 10 single E plasmas, are shown for three different viruses. M066 (black bars) is an NSI-sensitive isolate (strongly neutralized by three NAb pools), while NP1564 (white bars) and NP1453 (hatched bars) are the most resistant NSI and SI isolates. The dashed line indicates the 84% neutralization cutoff for sensitive viruses.

FIG. 3.

Differences in CD4 values of subtype E-infected patients with neutralization-sensitive and -resistant viruses. (A) All subtype E isolates were separated into two groups, based on neutralization sensitivity or resistance. The box plots show the distribution of concurrent patient CD4 values for each patient group, and the solid line represents the median. The boxed or shaded area displays the 25th to 75th percentiles, the top and bottom bars identify the 10th and 90th percentiles, and all plus signs represent CD4 counts falling outside the 10th and 90th percentiles. These data were analyzed by the Mann-Whitney U test (P < 0.001). (B) Box plots were prepared as described for panel A, except that CD4 counts for subtype E-infected patients having NAb-sensitive (S) or -resistant (R) isolates were further divided into four groups on the basis of SI or NSI viral phenotypes. There was a difference within the four groups as determined by a Kruskal-Wallis test (P = 0.008); the CD4 counts for patients with NSI-resistant viruses were significantly lower than those for patients with NSI-sensitive isolates (P = 0.013; Wilcoxon rank sums).