The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), led to a global public health crisis in which serological surveillance has been key to tracking viral spread. However, reports of false-positive serological results for unrelated infections in individuals with COVID-19 have raised concerns about antibody cross-reactivity across phylogenetically distant viruses [1], [2], [3]. Notably, potential cross-reactivity between SARS-CoV-2 and human immunodeficiency virus type 1 (HIV-1) has emerged as a critical issue, with studies describing instances where SARS-CoV-2 antigen/antibody interactions led to false-positive HIV-1 results across various immunoassays [3], [4], [5], [6], [7], [8].

Structural studies have indicated that the SARS-CoV-2 Spike (S) and HIV-1 Envelope (gp160) proteins share similar topology [9], [10], [11]. Both are class I fusion proteins extensively shielded by host-derived glycan molecules, which enables immune evasion by masking immunodominant epitopes and redirecting antibody responses toward non-protective regions [12], [13]. Other studies have indicated that SARS-CoV-2 spike antibody cross-reactivity is targeted towards the gp41 region of the HIV-1 Envelope [14], [15], potentially driven by sequence similarities in the N- and C-terminal segments of these proteins [9], [16], [17].

Within the gp41 region, the 2F5 epitope is a well-characterized site of vulnerability, known to be targeted by broadly neutralizing antibodies in HIV-1 infection. Interestingly, recent studies have reported that COVID-19 vaccination in HIV-1-infected individuals is associated with reduced plasma HIV-1 RNA levels and activation of the classical complement pathway [18], suggesting that anti-SARS-CoV-2 responses may influence HIV-1 through cross-reactive mechanisms. In this study, we investigated whether antibodies elicited by SARS-CoV-2 infection can recognize the HIV-1 2F5 epitope. By examining the extent and potential bidirectionality of this cross-reactivity, our findings aim to enhance the accuracy and the specificity of diagnostic approaches.