People living with HIV-1 (PLWH) on antiretroviral treatment (ART) present with delayed infection- and vaccine-induced humoral responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) compared with people without HIV-1 (PWOH). However, they eventually reach titers equivalent to those of PWOH.Differential coordination of SARS-CoV-2 Fc effector functions suggests that antibody responses are qualitatively variable in PLWH, with potential implications for vaccination.Intrahost diversity is more pronounced in ART-naive PLWH, who may contribute to the divergence of SARS-CoV-2 lineages and/or the emergence of variants of concern.Existing data on SARS-CoV-2 humoral immunity and intrahost diversity in PLWH supports the need to increase access to ART. Given the substantial number of people living with HIV-1 (PLWH), especially in sub-Saharan Africa, understanding the effectiveness of COVID-19 vaccines and antibody responses to SARS-CoV-2 infection and vaccination is essential. Additionally, the impact of pre-existing immunity against endemic human coronaviruses on SARS-CoV-2 responses in PLWH remains underexplored. Prolonged SARS-CoV-2 shedding, and enhanced intrahost diversity observed for PLWH, might be one of the driving forces behind SARS-CoV-2 evolution in Africa and should be further considered, with public health implications worldwide. The effect of COVID-19 on the high number of immunocompromised people living with HIV-1 (PLWH), particularly in Africa, remains a critical concern. Here, we identify key areas that still require further investigation, by examining COVID-19 vaccine effectiveness, and understanding antibody responses in SARS-CoV-2 infection and vaccination in comparison with people without HIV-1 (PWOH). We also assess the potential impact of pre-existing immunity against endemic human coronaviruses on SARS-CoV-2 responses in these individuals. Lastly, we discuss the consequences of persistent infection in PLWH (or other immunocompromised individuals), including prolonged shedding, increased viral diversity within the host, and the implications on SARS-CoV-2 evolution in Africa. The effect of COVID-19 on the high number of immunocompromised people living with HIV-1 (PLWH), particularly in Africa, remains a critical concern. Here, we identify key areas that still require further investigation, by examining COVID-19 vaccine effectiveness, and understanding antibody responses in SARS-CoV-2 infection and vaccination in comparison with people without HIV-1 (PWOH). We also assess the potential impact of pre-existing immunity against endemic human coronaviruses on SARS-CoV-2 responses in these individuals. Lastly, we discuss the consequences of persistent infection in PLWH (or other immunocompromised individuals), including prolonged shedding, increased viral diversity within the host, and the implications on SARS-CoV-2 evolution in Africa.