- In HIV infection, the primary target and most significantly depleted immune cells are the CD4+ T lymphocytes.
- HIV specifically infects these cells by binding to the CD4 receptor and co-receptors such as CCR5 or CXCR4.
- This leads to a progressive decline in the number and function of CD4+ T cells, which play a central role in orchestrating the immune response.

Key points:
- CD4+ T lymphocytes are crucial for coordinating immune responses, including activating other immune cells such as CD8+ cytotoxic T lymphocytes and B lymphocytes.
- HIV selectively infects and destroys CD4+ T cells, causing immunodeficiency.
- The depletion of CD4+ T cells leads to the weakening of the immune system and increases susceptibility to opportunistic infections and certain cancers.
- While other immune cells such as CD8+ T cells, B cells, and natural killer cells may also be affected functionally, their depletion is not as profound or direct as that seen with CD4+ T cells.

Thus, the hallmark of HIV infection is the significant loss of CD4+ T lymphocytes, making Option 3 the correct answer.

Reference: "Harrison's Principles of Internal Medicine," 20th Edition, Volume 2, Chapter 215/ Page 1372