More than three decades after human immunodeficiency virus 1 (HIV-1) was identified as the cause of AIDS, we still do not have an effective vaccine to stymie its global spread [
1]. Barriers to developing an effective HIV-1 vaccine include the following: (1) HIV-1 mutates rapidly and has a tremendous genetic diversity. In this regard, broadly neutralizing antibodies (bNAbs) can neutralize a broad range of HIV-1 isolates, but we do not know how to induce such bNAbs with a vaccine [
2]. Vaccines that induce non-broadly neutralizing HIV-1 Env-binding antibodies can afford partial protection against HIV-1/SHIV infection, but their efficacy needs to be substantially improved for clinical use [
3,
4]. (2) All HIV-1 envelope (Env) based vaccine candidates can only induce a short-lived antibody response. This is in striking contrast to vaccines currently in clinical use and may severely limit the long-term efficacy of HIV-1 vaccines [
5‐
8]. The mechanisms underlying this short duration of Env-antibody responses are not clear yet, but might be due to the failure of the Env glycoprotein to induce long-lived plasma cells [
9,
10]. (3) HIV-1 is a rapidly replicating lentivirus that can establish latent infection soon after infection [
11]. Thus an effective HIV-1 vaccine should elicit memory immune responses that can be mobilized fast (probably within a few days of infection) and sufficiently to block HIV-1 transmission through genital and rectal mucosa. Cytomegalovirus (CMV)-vectored HIV-1 vaccine might be able to elicit such a persistent and strong immune response [
12], but we do not know if and how other vaccine platforms can elicit such immune responses, especially at genital and rectal mucosa. (4) CD4
+ T cells play a pivotal role in forming memory immune response but are also target cells of HIV-1. An effective HIV-1 vaccine should induce potent cellular and humoral memory immune responses but avoid or limit stimulation of HIV-1 susceptible CD4
+ T cells, which is highlighted by the Step and Phambili clinical trials results [
13,
14]. Overcoming these barriers requires a multidisciplinary and multipronged approach, such as design of novel immunogens, development of better adjuvants, testing of multiple vaccination routes/schedules, and invention of novel delivery vehicles. Recent advances in immunology should be able to replace traditional adjuvants, such as alum, with an adjuvant that can preferentially promote protective responses from B cells, CD8
+ T cells, and/or natural killer cells (NK), but not activate CD4
+ T cells. Here, we will briefly review recent advances in the studies of such potential targeted adjuvants for HIV-1 vaccines. A thorough review is out of the scope of this short paper, and we will focus on three classes of molecules that we are studying: tumor necrosis factor superfamily (TNFSF) molecules, toll-like receptors (TLRs) agonists, and nucleotide-binding oligomerization domain-containing proteins (NODs) agonists.